CN107344940A - BTK inhibitor and application thereof - Google Patents

BTK inhibitor and application thereof Download PDF

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Publication number
CN107344940A
CN107344940A CN201710309938.5A CN201710309938A CN107344940A CN 107344940 A CN107344940 A CN 107344940A CN 201710309938 A CN201710309938 A CN 201710309938A CN 107344940 A CN107344940 A CN 107344940A
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alkyl
alkoxy
group
amino
cyano group
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CN107344940B (en
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刘兵
柏舜
杨悌平
周有柏
张英俊
郑常春
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Guangdong HEC Pharmaceutical
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention discloses BTK inhibitor and application thereof, specifically, the present invention provides a kind of heteroaryl compound or its stereoisomer, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug, and the pharmaceutical composition comprising the compounds of this invention；The invention also discloses the purposes of the compounds of this invention or its pharmaceutical composition in medicine is prepared, the medicine is used to treat autoimmune disease, inflammatory disease or proliferative diseases.

Description

BTK inhibitor and application thereof
Technical field
The present invention provides a kind of BTK inhibitor, discloses a series of compound and its pharmaceutical composition, also discloses this Class compound and its pharmaceutical composition be used to treating autoimmune disease or illness, heteroimmunity disease or illness including The cancer of lymthoma and the purposes of inflammatory disease.
Background technology
Bruton EGFR-TKs (Bruton's tyrosine kinase, BTK) be Tec kinase families it is a kind of it is non-by Body EGFR-TK, it is the key regulators of B cell development, activation, signal transduction and survival, in B-cell receptor (BCR) signal Played a significant role in transduction.When activating BCR, BTK is activated by other EGFR-TKs (such as Lyn and SYK) first, causes B Cell is bred to be activated with the required transcription factor of differentiation.In addition, BTK has also assisted in migrates and sticks phase with B cell The receptors signal transduction of pass, including Chemokine receptor CXCR4, CXCR5 and adhesion molecule (integrin).BTK kinases is lived Jump out of control, cause the random breeding of cell and trigger or promote canceration；The signal transduction of abnormal BCR mediations can cause mistake The B cell activation and/or the formation of pathogenic autoantibodies of regulation, this causes various autoimmune and/or diseases associated with inflammation.
BTK inhibitor Ibrutinib, which obtains FDA in November, 2013, to be ratified to be used to treat lymphoma mantle cell, 2 months 2014 Granted treatment chronic lymphocytic leukemia.Ibrutinib can be with cysteine residues selectivity, the irreversibility on BTK The strong covalent bond of formation, suppress the transmission of the cells survival signal of overacfivity in malignant B cell so as to reaching anticancer Effect.But Ibrutinib solubility is low, high with the Percentage bound (PPB) of plasma protein, oral administration biaavailability is low, directly leads Curative effect is not high after having caused patient orally.
Therefore, current BTK inhibitor still has much room for improvement.
Abstract of invention
The present invention provides a kind of heteroaryl compound, be used to treat as BTK inhibitor or suppress autoimmune disease or Illness, heteroimmunity disease or illness, inflammatory disease and cancer.
On the one hand, the present invention relates to a kind of compound, it is chemical combination shown in the compound or formula (II) as shown in formula (II) Stereoisomer, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvate, the metabolite of thing And pharmaceutically acceptable salt or prodrug：
Wherein：
X is C1-8Alkylidene or C1-8Sub- miscellaneous alkyl；X is optionally by 1,2,3,4,5,6,7,8,9,10,11,12,13 or 14 Individual RXSubstituted；
Each RXIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), C1-6 Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Alkoxy or C1-6Alkylamino；
Cy1 is C3-8Cycloalkyl, C3-8Cycloalkenyl group, C2-10Heterocyclic radical, C6-10Aryl or C1-9Heteroaryl；Cy1 optionally by 1, 2nd, 3,4,5,6,7,8,9 or 10 substituents are substituted, and the substituent is selected from RA1、RA2、RA3、RA4、RA5Or RA6；
Each RA1、RA2、RA3、RA4、RA5And RA6Independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, aldehyde radical, oxo (=O) ,-C (=O)-NRcRd,-S (=O)2-NRcRd、C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Alkane Epoxide, C1-6Alkylamino, halo C1-6Alkyl, halo C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, cyanogen The C of base substitution1-6Alkyl, the C of cyano group substitution1-6Alkoxy, the C of cyano group substitution1-6Alkylamino, the C of hydroxyl substitution1-6Alkyl, hydroxyl The C of base substitution1-6Alkoxy, the C of hydroxyl substitution1-6Alkylamino, C3-6Cycloalkyl, C3-6Cycloalkenyl group, C2-8Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C3-6Cycloalkyl C1-6Alkyl, C3-6Cycloalkenyl group C1-6Alkyl, C2-8Heterocyclic radical C1-6Alkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C3-6Cycloalkyl amino, C3-6Cycloalkenyl group amino, C2-8Heterocyclylamino group, C6-10Fragrant amino, C1-9Heteroaryl Base amino, C3-6Cycloalkyl oxy, C3-6Cycloalkenyl oxy, C2-8Heterocyclic radical epoxide, C6-10Aryloxy group, C1-9Heteroaryl epoxide, C3-6 Cycloalkyl oxy C1-6Alkyl, C3-6Cycloalkenyl oxy C1-6Alkyl, C2-8Heterocyclic radical epoxide C1-6Alkyl, C6-10Aryloxy group C1-6Alkane Base, C1-9Heteroaryl epoxide C1-6Alkyl, C3-6Cycloalkyl C1-6Alkoxy, C3-6Cycloalkenyl group C1-6Alkoxy, C2-8Heterocyclic radical C1-6Alkane Epoxide, C6-10Aryl C1-6Alkoxy or C1-9Heteroaryl C1-6Alkoxy；Each RA1、RA2、RA3、RA4、RA5And RA6Individually optional ground quilt 1st, 2,3,4,5 or 6 R1Substituted；
Each R1It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), C1-6 Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Alkoxy, C1-6Alkylamino, C1-6Alkyl sulphonyl, halo C1-6Alkyl, halo C1-6Alkane Epoxide, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, the C of cyano group substitution1-6Alkyl, the C of cyano group substitution1-6Alkoxy, The C of cyano group substitution1-6Alkylamino, the C of hydroxyl substitution1-6Alkyl, the C of hydroxyl substitution1-6Alkoxy or the C of hydroxyl substitution1-6Alkane ammonia Base；
Each RcAnd RdIt independently is hydrogen, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkyl, C3-8Cycloalkenyl group, C2-10It is miscellaneous Ring group, C6-10Aryl, C1-9Heteroaryl, C3-8Cycloalkyl C1-6Alkyl, C3-8Cycloalkenyl group C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C6-10Aryl C1-6Alkyl or C1-9Heteroaryl C1-6Alkyl；Each RcAnd RdIndividually optionally by 1,2,3,4,5 or 6 R2Substituted；
Each R2It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), C1-6 Alkyl, halo C1-6Alkyl, the C of hydroxyl substitution1-6Alkyl, the C of cyano group substitution1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Alcoxyl Base or C1-6Alkylamino；
S is 0,1,2,3,4,5 or 6；
Hy is C3-8Cycloalkylidene, C3-8Sub- cycloalkenyl group, C2-15Sub- heterocyclic radical, C6-10Arlydene or C1-9Inferior heteroaryl；
RBThe C substituted for cyano group or cyano group1-6Alkyl；Or RBFor following subformula：
Ry1、Ry4And Ry3It is each independently hydrogen, halogen, methyl or cyano group；
Cy3 is C3-6Cycloalkylidene, C3-6Sub- cycloalkenyl group, C2-6Sub- heterocyclic radical, C6-10Arlydene or C1-6Inferior heteroaryl；
Each R3、R3aAnd R12It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, carboxyl or C1-3Alkyl；
Each R4、R3b、R5、R13And R14It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, carboxyl ,-(CRiRk)n-NRvRw、 C1-3Alkyl, halo C1-3Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Alkoxy C1-4Alkyl, C1-3Alkylamino C1-3Alkyl, C3-6Cycloalkanes Base, C3-6Cycloalkyl C1-3Alkyl, C2-6Heterocyclic radical, C2-6Heterocyclic radical C1-3Alkyl, C6-10Aryl, C6-10Aryl C1-3Alkyl, C1-6It is miscellaneous Aryl or C1-6Heteroaryl C1-3Alkyl；
R18And R19It is each independently hydrogen, deuterium, C1-4Alkyl, halo C1-3Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-3Alcoxyl Base C1-3Alkyl, C1-3Alkylamino C1-3Alkyl, C3-6Cycloalkyl, C3-6Cycloalkyl C1-3Alkyl, C2-6Heterocyclic radical C1-3Alkyl, C6-10Virtue Base C1-3Alkyl or C1-6Heteroaryl C1-3Alkyl；
Each R27、R28And R30It independently is hydrogen, C1-4Alkyl, halo C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-3Alkoxy C1-3Alkyl, C1-3Alkylamino C1-3Alkyl, C3-6Cycloalkyl, C3-6Cycloalkyl C1-3Alkyl, C2-6Heterocyclic radical C1-3Alkyl, C6-10Aryl C1-3Alkyl or C1-6Heteroaryl C1-3Alkyl；
Each RiAnd RkIndependently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), C1-3Alkyl, C2-4Alkenyl or C2-4Alkynyl；
N is 1,2,3,4,5 or 6；
Each R3c、R3d、RvAnd RwIt independently is hydrogen, deuterium, C1-4Alkyl, the C of cyano group substitution1-3Alkyl, halo C1-3Alkyl, C1-3 Alkoxy C1-3Alkyl, C3-6Cycloalkyl, C6-10Aryl, C1-6Heteroaryl, C2-6Heterocyclic radical or C2-6Heterocyclic radical C1-3Alkyl；Or Rv、Rw Formed together with the N atoms being attached thereto by 3-8 former molecular heterocycle；With
Each X, RX、Cy1、Cy3、RA1、RA2、RA3、RA4、RA5、RA6、Rc、Rd、R1、R2、Hy、RB、R3、R3a、R3b、R3c、R3d、 R4、R5、R12、R13、R14、R18、R19、R27、R28、R30、Ri、Rk、RvAnd RwIndividually optionally by 1,2,3,4,5,6,7,8,9 or 10 Individual substituent is substituted, and the substituent is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), C1-6Alkyl, C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Alkyl-C (=O)-, cyano group substitution C1-6Alkyl-C (=O)-, C1-6Alkylamino, NH2- S (=O)2-、C1-6Alkyl-NH-S (=O)2-、NH2- S (=O)2-C1-6Alkyl, halo C1-6Alkane Base, the C of hydroxyl substitution1-6Alkyl, the C of cyano group substitution1-6Alkyl, C3-6Cycloalkyl, C2-8Heterocyclic radical, C6-10Aryl, C6-10Aryloxy group Or C6-10Aryl C1-6Alkoxy.
Some of embodiments are Hy C3-6Cycloalkylidene, C3-6Sub- cycloalkenyl group, C6-10Arlydene, C1-6Inferior heteroaryl Or Hy is following subformula：
Wherein：
p1And p2It is each independently 0,1 or 2.
Some of embodiments are that Hy is following subformula：
Some of embodiments are RBThe C substituted for cyano group or cyano group1-4Alkyl；Or RBFor following subformula：
Some of embodiments are that the present invention relates to a kind of compound, and it is the compound or formula as shown in formula (IIa) (IIa) stereoisomer, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, the solvent of compound shown in Compound, metabolite and pharmaceutically acceptable salt or prodrug：
Wherein,
X and Cy1 has implication as described in the present invention.
Some of embodiments are Cy1 C3-6Cycloalkyl, C3-6Cycloalkenyl group, C2-8Heterocyclic radical, C6-10Aryl or C1-9It is miscellaneous Aryl；Cy1 is optionally substituted by 1,2,3,4,5,6,7,8,9 or 10 substituent, and the substituent is selected from RA1、RA2、RA3、 RA4、RA5Or RA6；Wherein RA1、RA2、RA3、RA4、RA5And RA6With implication as described in the present invention.
Some of embodiments are that Cy1 is cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclobutane base, cyclopentene Base, cyclopentadienyl group, cyclohexenyl group, cyclohexadienyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, 1- oxos are thio Morpholinyl, 1,1- dioxothiomorpholinyls or iso-indoles -1,3- diketone -4- bases；Or Cy1 is following subformula：
Cy1 is optionally substituted by 1,2,3,4,5,6,7,8,9 or 10 substituent, the substitution Base is selected from RA1、RA2、RA3、RA4、RA5Or RA6；Wherein RA1、RA2、RA3、RA4、RA5And RA6With implication as described in the present invention.
Some of embodiments are that the present invention relates to a kind of compound, and it is the compound or formula as shown in formula (IV) (IV) stereoisomer, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, the solvent of compound shown in Compound, metabolite and pharmaceutically acceptable salt or prodrug：
Wherein：
Y1For N or CRA1；
Y2For N or CRA2；
Y3For N or CRA3；
X、RA1、RA2、RA3、RA4And RA5With implication as described in the present invention.
Some of embodiments are that X is-(CR31R32)r-、-(CR31R32)r-O-(CR33R34)t-、-(CR31R32)r-C (=O)-(CR33R34)t-、-(CR31R32)r- S (=O)2-(CR33R34)t-、-(CR31R32)r-N(R35)-(CR33R34)t- ,-C (= O)-N(R35)-(CR33R34)t-、-(CR31R32)r-N(R35)-C (=O)-or-(CR31R32)r-N(R35)-S (=O)2-；
Each r independently is 1,2,3 or 4；
Each t independently is 0,1,2 or 3；
Each R31、R32、R33And R34It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxygen Generation (=O), C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-3Alkoxy or C1-3Alkylamino；With
Each R35It independently is hydrogen, deuterium, C1-4Alkyl, C2-4Alkenyl or C2-4Alkynyl.
Some of embodiments are that X is-CH2-、-(CH2)2-、-(CH2)3-、-C(CH3)2-、-CH2-C(CH3)2-、-C (CH3)(OH)-、-CH2-O-、-CH2-O-CH2-、-C(CH3)2-O-、-C(CH3)(OH)-O-、-CH(CH3)-O-CH2-、-C (CH3)2-O-CH2-、-CH2-NH-、-CH2-NH-CH2-、-C(CH3)2-NH-、-CH(CH3)-NH-CH2-、-C(CH3)2-NH- CH2-、-C(CH3) (OH)-NH- ,-C (=O)-NH- ,-C (=O)-NH-CH2-、-CH2- NH-C (=O)-,-CH2- NH-S (= O)2-、-(CH2)2- NH-S (=O)2-、-CH(CH3)-NH-S (=O)2- or-C (CH3)2- NH-S (=O)2-。
Some of embodiments are each RA1、RA2、RA3、RA4、RA5And RA6It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyanogen Base, hydroxyl, nitro, amino, carboxyl, aldehyde radical, oxo (=O) ,-C (=O)-NRcRd,-S (=O)2-NRcRd、C1-4Alkyl, C2-4 Alkenyl, C2-4Alkynyl, C1-4Alkoxy, C1-4Alkylamino, halo C1-4Alkyl, halo C1-4Alkoxy, C1-4Alkoxy C1-4Alkyl, C1-4Alkylamino C1-4Alkyl, the C of cyano group substitution1-4Alkyl, the C of cyano group substitution1-4Alkoxy, the C of cyano group substitution1-4Alkylamino, hydroxyl The C of base substitution1-4Alkyl, the C of hydroxyl substitution1-4Alkoxy, the C of hydroxyl substitution1-4Alkylamino, C3-6Cycloalkyl, C3-6Cycloalkenyl group, C2-6Heterocyclic radical, C6-10Aryl, C1-6Heteroaryl, C3-6Cycloalkyl C1-3Alkyl, C3-6Cycloalkenyl group C1-3Alkyl, C2-6Heterocyclic radical C1-3Alkane Base, C6-10Aryl C1-3Alkyl, C1-6Heteroaryl C1-3Alkyl, C3-6Cycloalkyl amino, C3-6Cycloalkenyl group amino, C2-6Heterocyclic radical ammonia Base, C6-10Fragrant amino, C1-6Heteroaryl amino, C3-6Cycloalkyl oxy, C3-6Cycloalkenyl oxy, C2-6Heterocyclic radical epoxide, C6-10Fragrant oxygen Base, C1-6Heteroaryl epoxide, C3-6Cycloalkyl oxy C1-3Alkyl, C3-6Cycloalkenyl oxy C1-3Alkyl, C2-6Heterocyclic radical epoxide C1-3Alkane Base, C6-10Aryloxy group C1-4Alkyl, C1-6Heteroaryl epoxide C1-3Alkyl, C3-6Cycloalkyl C1-3Alkoxy, C3-6Cycloalkenyl group C1-3Alcoxyl Base, C2-6Heterocyclic radical C1-3Alkoxy, C6-10Aryl C1-4Alkoxy or C1-6Heteroaryl C1-4Alkoxy；Each RA1、RA2、RA3、RA4、RA5 And RA6Individually optionally by 1,2,3,4,5 or 6 R1Substituted；
Wherein R1、RcAnd RdWith implication as described in the present invention.
Some of embodiments are each R1Independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, oxo (=O), C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Alkoxy, C1-4Alkylamino, C1-4Alkyl sulphonyl, halo C1-4Alkyl, halo C1-4Alkoxy, C1-4Alkoxy C1-4Alkyl, C1-4Alkylamino C1-4Alkyl, the C of cyano group substitution1-4Alkyl, cyanogen The C of base substitution1-4Alkoxy, the C of cyano group substitution1-4Alkylamino, the C of hydroxyl substitution1-4Alkyl, the C of hydroxyl substitution1-4Alkoxy or The C of hydroxyl substitution1-4Alkylamino.
Some of embodiments are each RcAnd RdIt independently is hydrogen, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-6Cycloalkanes Base, C3-6Cycloalkenyl group, C2-6Heterocyclic radical, C6-10Aryl, C1-5Heteroaryl, C3-6Cycloalkyl C1-3Alkyl, C3-6Cycloalkenyl group C1-3Alkyl, C2-6Heterocyclic radical C1-3Alkyl, C6-10Aryl C1-3Alkyl or C1-5Heteroaryl C1-3Alkyl；Each RcAnd RdIndividually optionally by 1,2,3, 4th, 5 or 6 R2Substituted；
Wherein R2With implication as described in the present invention.
Some of embodiments are each R2Independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, oxo (=O), C1-3Alkyl, C2-3Alkenyl, C2-3Alkynyl, C1-3Alkoxy or C1-3Alkylamino.
Some of embodiments are each RA1、RA2、RA3、RA4、RA5And RA6It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyanogen Base, hydroxyl, nitro, amino, carboxyl, aldehyde radical, oxo (=O), Ph-NH-C (=O)-, halogen substitution Ph-NH-C (=O)-, Ph-NH-S (=O)2-, methyl, ethyl, propyl group, isopropyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, methylamino, two Methylamino, ethylamino, halo C1-3Alkyl, halo C1-3Alkoxy, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, oxa- ring fourth Base, azelidinyl, tetrahydrofuran base, pyrrolidinyl, THP trtrahydropyranyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, Phenyl, indenyl, phenoxy group, thiazol-2-yl epoxide, thiazole-4-yl epoxide, thiazole -5- bases epoxide, pyridine radicals epoxide, pyrimidine radicals Epoxide, pyrazinyl epoxide, pyridazinyl epoxide, benzyloxy, fluorinated benzyloxy, chloro benzyloxy, benzyloxy, the first sulphur of cyano group substitution Benzyloxy, phenyl ethoxy, phenoxymethyl, fluorinated phenoxy methyl, chloro phenoxymethyl, the pyridine -2- of acyl group substitution Ylmethoxy, pyridin-3-yl methoxyl group, pyridin-4-yl methoxyl group, pyrimidinylmethoxy, pyrazine ylmethoxy, pyridazinyl methoxy Base, thiazol-2-yl methoxyl group, thiazole-4-yl methoxyl group, thiazole -5- ylmethoxies, 2- methylthiazol -5- ylmethoxies or 5- Methylthiazol -2- ylmethoxies.
One aspect of the present invention is related to a kind of pharmaceutical composition, includes compound of the present invention or its alloisomerism Body, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically may be used The salt or prodrug of receiving.
Some of embodiments are that pharmaceutical composition of the present invention further includes pharmaceutically acceptable load Body, excipient, diluent, at least one of assistant agent or medium.
Some of embodiments are that pharmaceutical composition of the present invention further includes additional therapeutic agent, and it is selected From chemotherapeutic agent, cytotoxic drug, antibody drug, signal transduction inhibitor, chemotherapeutics, antiproliferative, anti-inflammatory agent, exempt from Epidemic disease conditioning agent or immunodepressant, neurotrophic factor, the activating agent for treating angiocardiopathy, for treating diabetes Activating agent and the activating agent for treating autoimmune disease.
Other embodiment is pharmaceutical composition of the present invention, wherein the additional therapeutic agent is selected from according to Shandong For Buddhist nun, leflunomide, Carfilzomib, Rituximab, difficult to understand, Cetuximab, Victibix, matuzumab, Buddhist nun's trastuzumab, Herceptin, Nivolumab, bendamustine, fludarabine, Imatinib, Dasatinib, Ji Fei are replaced Buddhist nun, nilotinib, Erlotinib, Lapatinib, Sorafenib, Sutent, Conmana, hydrochloric acid Conmana, come that and replace Buddhist nun, canertinib, ZD6474, Axitinib, Xi Li for Buddhist nun, according to pyrrole for Buddhist nun, west for Buddhist nun, tropsch imatinib, Luso for Buddhist nun, Baricitinib、Pacritinib、Momelotinib、Peficitinib、Obinutuzumab、Acalabrutinib、 Spebrutinib、inotuzumab ozogamicin、Obinutuzumab、Duvelisib、Idelalisib、PRN-1008、 HM-71224、ONO-4059、BGB-3111、ML-319、TAS-5315、AT-9283、X-022、AC-0025、NS-018、INCB- 39110th, JTE-052, R-348 or combinations thereof.
One aspect of the present invention is related to compound of the present invention or pharmaceutical composition of the present invention is preparing medicine In purposes, wherein the medicine be used for prevent, handle, treat or mitigate autologous patient immunological diseases, inflammatory disease, cancer or Other diseases.
Some of embodiments are that autoimmune disease of the present invention is lupus, multiple sclerosis, muscle contracting Lateral sclerosis, rheumatoid arthritis, psoriasis, type i diabetes, the complication caused by organ transplant, foreign matter transplanting, glycosuria Disease, cancer, asthma, atopic dermatitis, AITD, ulcerative colitis, Crohn disease, Alzheimer Disease, leukaemia or lymthoma.
Some of embodiments are that inflammatory disease of the present invention is keratitis, rhinitis, stomatitis, parotitis, pharynx Inflammation, tonsillitis, tracheitis, bronchitis, pneumonia, myocarditis, gastritis, enterogastritis, cholecystitis or appendicitis.
Some of embodiments are, cancer of the present invention or other diseases be various B cell malignant tumours (including Small lymphocyte lymthoma (SLL), ALL (ALL), chronic lymphocytic leukemia (CLL), acute bone Myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute promyelocytic leukemia (APL), chronic granulocyte is white Blood disease, diffusivity large B cell lymphoid tumor (DLBCL), intravascular large B cell lymphoma, lymphoma primary effusion (PEL), Waldenstrom's macroglobulinemia (Waldenstrom Macroglobulinemia), follicular lymphoma (Follicular Lymphom), Huppert's disease and lymphoma mantle cell (MCL)) and other suppress the disease benefited to patient of kinase activities Disease.
Some of embodiments are that other protein kinase mediated diseases of the present invention are metastatic carcinoma, brain tumor, wing Guang cancer, stomach cancer, oophoroma, cancer of pancreas, breast cancer, head and neck cancer, cervix cancer, carcinoma of endometrium, the carcinoma of the rectum, liver cancer, kidney, lung Cancer, cancer of the esophagus, prostate cancer, thyroid cancer, osteocarcinoma, cutaneum carcinoma, colon cancer, female reproductive tract knurl, lymthoma, multiple marrow Cancer, glioblastoma, myeloproliferative disease, atherosclerosis, pulmonary fibrosis and the carcinoma of testis of knurl, CNS (cental system).
On the other hand, the present invention relates to one kind to use compound of the present invention or pharmaceutical composition of the present invention To prepare the purposes of the medicine for suppression or regulatory protein kinase activity.
Some of embodiments are that protein kinase of the present invention is BTK.
On the one hand, the present invention relates to prepare formula (I), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), The intermediate for the compound that formula (IIIc) or formula (IV) are included.
Another aspect of the present invention is related to formula (I), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula Or the method for preparation, separation and the purifying of compound that is included of formula (IV) (IIIc).
Content noted earlier only outlines certain aspects of the invention, but be not limited to these aspect and it is otherwise in Appearance will make more specific complete description below.
Detailed description of the invention book
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation enclosed.This Invention is intended to cover all replacement, modification and equivalent technical solutions, and they are included in the present invention defined such as claim In the range of.Those skilled in the art will appreciate that many can be used in similar or equivalent method of the present invention and material The practice present invention.The present invention is not limited to method of the present invention and material.In document, patent and the similar material combined One or more or contradict in the case of (include but is not limited to defined in term, term application, institutes different from the application Technology of description, etc.), it is defined by the application.
It will further be appreciated that some features of the present invention, are clearly visible, are carried out in multiple independent embodiments Description, but can also be provided in combination in single embodiment.Conversely, the various features of the present invention, for brevity, It is described, but can also be provided individually or with arbitrarily suitable sub-portfolio in single embodiment.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
Unless otherwise indicated, following definition used in the present invention should be applied.For purposes of the present invention, chemical element With periodic table of elements CAS versions, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can With reference to " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito: 1999, and " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March,John Wiley&Sons,New York:Description in 2007, entire contents are incorporated by reference into the present invention.
There is obvious conflict unless otherwise indicated or in context, article " one " used herein, " one (kind) " " described " is intended to include " at least one " or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to has more than one Component be taken into account in the embodiment of the embodiment and use or use.
Term " study subject " used in the present invention refers to animal.Typically described animal is mammal.It is tested right As, such as also refer to primate (such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described by It is people to try object.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.
Term "comprising" is open language, that is, includes the content specified by the present invention, but be not precluded from otherwise Content.
" stereoisomer " refers to there is identical chemical constitution, but the spatially different change of arrangement mode of atom or group Compound.Stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..
" chirality " be with its mirror image can not overlapping property molecule；And " achirality " refer to can be with overlapping with its mirror image Molecule.
" enantiomter " refers to that two of a compound can not isomers that is overlapping but being mutually mirror.
" diastereoisomer " refers to have two or more chiral centres and its molecule not alloisomerism of mirror image each other Body.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral quality and reactivity.Diastereoisomer mixes Compound can be operated such as electrophoresis and chromatogram, such as HPLC by high resolution analysis to separate.
Stereochemical definitions used in the present invention and rule typically follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley&Sons, Inc.,New York,1994。
Many organic compounds exist with optical active forms, i.e., they, which have, rotates the plane of linearly polarized light Ability.When describing optically active compound, represent molecule on one or more hand using prefix D and L or R and S The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols rotated for linearly polarized light caused by appointed compound, Wherein (-) or l represent that compound is left-handed.Prefix is (+) or d compound is dextrorotation.A kind of specific alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter:50 mixtures Referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereoselectivity or stereospecificity when, It may occur in which such case.
Any asymmetric atom (for example, carbon etc.) that the present invention discloses compound can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration be present.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of there is at least 50% enantiomeric excess, at least at least 60% enantiomeric excess, 70% enantiomer mistake Amount, at least at least 80% enantiomeric excess, at least 90% enantiomeric excess, 95% enantiomeric excess, or at least 99% enantiomer It is excessive.
According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) deposits .Chiral synthon or chiral reagent can be used to prepare for optically active (R)-or (S)-isomers, or be torn open using routine techniques Point.If compound contains a double bond, substituent may be E or Z configurations；If contain dibasic cycloalkanes in compound Base, the substituent of cycloalkyl may have cis or trans configuration.
The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.
The racemic modification of any gained end-product or intermediate can be passed through into those skilled in the art with known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Thing can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomers can be prepared by asymmetric syntheses, for example, Jacques is referred to, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。
What term " dynamic isomer " or " tautomeric form " referred to have different-energy can build (low by low energy Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical balance of dynamic isomer.Unless otherwise noted, all tautomeric forms of the compounds of this invention are all in the present invention Within the scope of.
As described in the invention, compound of the invention optionally can be substituted by one or more substituents, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included. It should be appreciated that this term can exchange use to " optionally substituting " this term with " substituted or non-substituted ".In general, art Language is " substituted " to represent that institute is substituted to one or more of structure hydrogen atom by specific substituent.Unless other aspect tables Bright, an optional substituted radical can be substituted in each commutable position of group.When in given structural formula not Only a position can be substituted by one or more substituents selected from specific group, then substituent can with identical or different Substitute in each position.Wherein described substituent can be, but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitre Base, amino, carboxyl, alkyl, alkoxy, alkoxyalkyl, alkyloxy-alkoxy, alkoxy alkylamino, aryloxy group, heteroaryl oxygen Base, heterocyclic radical epoxide, alkoxy aryl, heteroarylalkoxy, heterocyclylalkoxy, cycloalkyl alkoxy, alkylamino, alkylamino Alkyl, alkylamino alkylamino, cycloalkyl amino, amino-n-cycloalkyl, alkylthio group, haloalkyl, halogenated alkoxy, hydroxyl substitution Alkyl, hydroxyl substitution alkylamino, cyano group substitution alkyl, cyano group substitution alkoxy, cyano group substitution alkylamino, amino Substituted alkyl, alkyl acyl, miscellaneous alkyl, cycloalkyl, cycloalkenyl group, cycloalkyl-alkyl, heterocyclic radical, cycloheteroalkylalkyl, heterocyclic radical Acyl group, aryl, aryl alkyl, fragrant amino, heteroaryl, heteroaryl alkyl, heteroaryl amino, amide groups, sulfonyl, aminosulfonyl Base etc..
In addition, it is necessary to explanation, unless otherwise explicitly point out, used describing mode in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, it both may be used To refer in different groups, do not influence mutually, can also represent in phase between expressed specific option between same-sign In same group, do not influenceed mutually between expressed specific option between same-sign.
In each several part of this specification, the substituent that the present invention discloses compound discloses according to radical species or scope.It is special Do not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.For example, term “C1-C6Alkyl " or " C1-6Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each several part of the present invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.If for example, the structure needs linking group and for being somebody's turn to do The Markush group definition of variable lists " heterocyclic radical " or " aryl ", then it should be understood that should " heterocyclic radical " or " aryl " difference Represent the sub- heterocyclyl groups or arylene group of connection.Unless otherwise indicated, the ways of writing of linker structural formula is for even Connecing the direction of base does not have any hint, such as alkylidene, sub- miscellaneous alkyl or sub- heterocyclic radical, as long as its connected mode is reasonable and stably 's.
Terminology used in the present invention " alkyl " or " alkyl group ", expression contain 1 to 20 carbon atom, the straight chain of saturation or Side chain univalent hydrocarbyl group；Wherein described alkyl group is optionally substituted by the substituent that one or more present invention describe. Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1-12 carbon Atom；In one embodiment, alkyl group contains 1-8 carbon atom；In another embodiment, alkyl group contains 1-6 Individual carbon atom；In yet another embodiment, alkyl group contains 1-4 carbon atom；Also in one embodiment, alkyl group contains There is 1-3 carbon atom.
The example of alkyl group includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n- Pr、-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,- CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), the tert-butyl group (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl groups (- CH (CH3)CH2CH2CH3), 3- amyl groups (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl isophthalic acids-butyl (- CH2CH2CH(CH3)2), 2- first Base -1- butyl (- CH2CH(CH3)CH2CH3), etc..
Term " alkylidene " represents to remove from the straight or branched alkane of saturation the saturation obtained by two hydrogen atoms Divalent alkane base group；Wherein described alkylidene group is optionally substituted by the substituent that one or more present invention describe. Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In one embodiment, alkylidene group contains 1-8 Individual carbon atom；In one embodiment, alkylidene group contains 1-6 carbon atom；In another embodiment, alkylidene group Contain 1-4 carbon atom；In yet another embodiment, alkylidene group contains 1-3 carbon atom；Also in one embodiment, Alkylidene group contains 1-2 carbon atom.Such example includes methylene (- CH2-), ethylidene (- CH2CH2-), propylidene (-CH2CH2CH2-) ,-CH (CH3)CH2- ,-C (CH3)2- ,-C (CH3) (OH)-,-CH2CH2CH(CH3)-,-CH2CH2C (CH3)2- ,-(CH2)4- etc..
Term " miscellaneous alkyl " represents stable straight or branched alkyl, and wherein at least one C atoms are chosen individually optionally From N, O, P, S hetero atom is substituted, wherein N, O, P, and S can be located at any interior location of miscellaneous alkyl or positioned at the group with dividing The position that is connected of remainder of son, the C atoms in miscellaneous alkyl are optionally substituted to obtain C (=O) group by oxygen atom.Alkane Base is as defined herein.Some of embodiments are that " miscellaneous alkyl " is the side chain or straight chain (1-9 of 1-10 atom Carbon atom and selected from N, O, P, S 1-3 hetero atom, optionally substitute to obtain picture by one or more oxygen atoms in this S or P SO, SO2, PO, PO2Group)；Other embodiment is that miscellaneous alkyl is the side chain or straight chain (1-7 carbon of 1-8 atom Atom and selected from N, O, P, S 1-3 hetero atom, optionally substitute to obtain picture by one or more oxygen atoms in this S or P SO, SO2, PO, PO2- ,-C (CH；Other embodiment is that miscellaneous alkyl is the side chain or straight chain (1-5 carbon of 1-6 atom Atom and selected from N, O, P, S 1-3 hetero atom, optionally substitute to obtain picture by one or more oxygen atoms in this S or P SO, SO2, PO, PO2Group)；Other embodiment is that miscellaneous alkyl is the side chain or straight chain (1-3 carbon of 1-4 atom Atom and selected from N, O, P, S 1-3 hetero atom, optionally substitute to obtain picture by one or more oxygen atoms in this S or P SO, SO2, PO, PO2Group)；Other embodiment is that miscellaneous alkyl is the side chain or straight chain (1-2 carbon of 1-3 atom Atom and selected from N, O, P, S 1-2 hetero atom, optionally substitute to obtain picture by one or more oxygen atoms in this S or P SO, SO2, PO, PO2Group).The example of miscellaneous alkyl includes, but is not limited to ,-CH2-CH2-O-CH3,-CH2-CH2-NH- CH3,-CH2-CH2-N(CH3)-CH3,-CH2-S-CH2-CH3,-CH2-CH2-S(O)-CH3,-CH2- C=N-OCH3,-NH-CH2- CH3,-NH-CH2- C (=O)-NH-CH2-CH3,-NH-CH (C (CH3)3)-C (=O)-NH-CH2-CH3,-NH-CH (CH (CH3)2)-C (=O)-NH-CH2-CH3,-NH-CH2-CH2-CH3,-NH-CH2-CH2-O-CH3,-O-CH2-CH2-O-CH3,-CH2- NH-(CH2)2- NH-S (=O)2CH3Deng.
Term " sub- miscellaneous alkyl " refers to that miscellaneous alkyl removes the divalent group that a hydrogen atom obtains；Wherein described sub- miscellaneous alkyl Group is optionally substituted by the substituent that one or more present invention describe.The example of sub- miscellaneous alkyl includes, but and unlimited In ,-O- ,-NH- ,-N (CH3)-,-C (=O)-,-S- ,-S (=O)-,-S (=O)2- ,-CH2- O- ,-CH2-O-CH2- ,-C (CH3)2- O- ,-C (CH3) (OH)-O- ,-CH2- NH- ,-CH2-NH-CH2- ,-C (CH3)2- NH- ,-C (CH3) (OH)-NH- ,-C (=O)-NH- ,-C (=O)-NH-CH2- ,-CH2- NH-C (=O)-,-CH2- NH-S (=O)2-, etc..
Term " alkenyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is a carbon-to-carbon sp2Double bond, wherein, the alkenyl group can be retouched optionally by one or more present invention The substituent stated is substituted, and it includes " cis " and " tans " positioning, or " E " and " Z " positioning.In one embodiment, Alkenyl group includes 2-8 carbon atom；In another embodiment, alkenyl group includes 2-6 carbon atom；In another embodiment party In case, alkenyl group includes 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (- CH=CH2), Pi-allyl (- CH2CH=CH2), acrylic (CH3Hemocyanin3- C (=O)-CH=CH-) etc..
Straight or branched monovalent hydrocarbon of term " alkynyl " expression containing 2-12 carbon atom, wherein at least one carbon- The keys of carbon sp tri-.
Term " alkoxy " represents that alkyl group is connected by oxygen atom with molecule remainder, and wherein alkyl group has Implication as described in the present invention.The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO、-OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,- OCH(CH3)2) etc..
Term " alkyl amino " or " alkylamino " include " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino base Group is separately substituted by one or two alkyl group.Some of embodiments are that alkyl amino is one or two C1-6Alkyl is connected to the alkylamino group of the lower level on nitrogen-atoms.Other embodiment is that alkyl amino is C1-3's The alkylamino group of lower level.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, such reality Example includes, but is not limited to, N- methylaminos, N- ethylaminos, N, N- dimethylaminos, N, N- lignocaines etc..
Term " alkyl sulphonyl " refers to alkyl-S (=O)2-, wherein alkyl group has implication as described in the present invention. Such example includes, but is not limited to, CH3- S (=O)2-、CH3CH2- S (=O)2-, etc..
Term " alkoxyalkyl " represents that alkyl group is substituted by one or more alkoxy bases, wherein alkyl group There is implication as described in the present invention with alkoxy base, such example includes, but is not limited to, methoxy, methoxy Base ethyl, ethoxyl methyl, ethoxyethyl group etc..
Term " alkyl amino alkyl " represents that alkyl group is substituted by one or more alkylamino radicals, wherein alkyl group There is implication as described in the present invention with alkylamino radicals.
Term " haloalkyl " represents that alkyl group is substituted by one or more halogen atoms, and such example includes, But it is not limited to ,-CH2F ,-CHF2,-CF3,-CH2Cl ,-CHCl2,-CCl3,-CH2CF3,-CH2CH2CF3Deng.
Term " halogenated alkoxy " represents that alkoxy base is substituted by one or more halogen atoms；Wherein alkoxy base Group has implication as described in the present invention.
Term " alkyl of cyano group substitution " represents that alkyl group is substituted by one or more cyano group；" cyano group substitutes term Alkoxy " represent alkoxy base substituted by one or more cyano group；Term " alkylamino of cyano group substitution " represents alkane ammonia Base group is substituted by one or more cyano group；Wherein alkyl, alkoxy and alkylamino radicals have and contained as described in the present invention Justice.
Term " alkyl of hydroxyl substitution " represents that alkyl group is substituted by one or more hydroxyls；" hydroxyl substitutes term Alkoxy " represent alkoxy base substituted by one or more hydroxyls；Term " alkylamino of hydroxyl substitution " represents alkane ammonia Base group is substituted by one or more hydroxyls；Wherein alkyl, alkoxy and alkylamino radicals have and contained as described in the present invention Justice.
Term " cycloalkyl " represented containing 3-12 carbon atom, monovalent or multivalence the monocyclic, bicyclic or tricyclic body of saturation System.In one embodiment, cycloalkyl includes 3-10 carbon atom；In another embodiment, it is former to include 3-8 carbon for cycloalkyl Son；In yet another embodiment, cycloalkyl includes 3-6 carbon atom.The group of naphthene base is optionally by one or more sheets The described substituent of invention is substituted.Such example includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopenta, hexamethylene Base, suberyl, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, etc..
Term " cycloalkyl-alkyl " refers to that alkyl group is substituted by one or more groups of naphthene base；Wherein cycloalkyl and alkane Base group has implication as described in the present invention.
Term " cycloalkyl alkoxy " refers to that alkoxy base is substituted by one or more groups of naphthene base；Wherein cycloalkyl There is implication as described in the present invention with alkoxy base.
Term " cycloalkyl amino " refers to that amino group is substituted by one or two group of naphthene base；Wherein group of naphthene base With implication as described in the present invention.
Term " cycloalkyl oxy " refers to the cycloalkyl optionally substituted, as defined herein, is connected on oxygen atom, And it is connected by oxygen atom with molecule remainder, wherein group of naphthene base has implication as described in the present invention.
Term " cycloalkyloxyalkyl " refers to that alkyl group is substituted by one or more cycloalkyl oxy groups, its middle ring Alkyl oxy and alkyl group have implication as described in the present invention.
Term " cycloalkenyl group " represented containing 3-12 carbon atom, 3-8 carbon atom or 3-6 carbon atom, monovalent Or multivalence, monocyclic, the bicyclic or three-ring system of non-aromatic, including at least a carbon-carbon double bond.
Term " cycloalkenyl alkyl " refers to that alkyl group is substituted by one or more cycloalkenyl groups；Wherein cycloalkenyl group and alkane Base group has implication as described in the present invention.
Term " cycloalkenyl group alkoxy " refers to that alkoxy base is substituted by one or more cycloalkenyl groups；Wherein cycloalkenyl group There is implication as described in the present invention with alkoxy base.
Term " cycloalkenyl group amino " refers to that amino group is substituted by one or two cycloalkenyl groups；Wherein cycloalkenyl groups With implication as described in the present invention.
Term " cycloalkenyl oxy " refers to the cycloalkenyl group optionally substituted, as defined herein, is connected on oxygen atom, And it is connected by oxygen atom with molecule remainder, wherein cycloalkenyl groups have implication as described in the present invention.
Term " cycloalkenyl oxy alkyl " refers to that alkyl group is substituted by one or more cycloalkenyl oxy groups, its middle ring Alkenyl epoxide and alkyl group have implication as described in the present invention.
Term " heterocyclic radical " and " heterocycle " are used interchangeably here, all referring to the saturation comprising 3-15 annular atom or portion It is point undersaturated monocyclic, bicyclic or tricyclic, wherein do not include aromatic rings in monocyclic, bicyclic or tricyclic, and at least one annular atom Selected from nitrogen, sulphur and oxygen atom.Unless otherwise indicated, heterocyclic radical can be carbon-based or nitrogen base, and-CH2- group can be optionally By-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- oxides.The nitrogen-atoms of ring can be optionally by oxygen It is melted into N- oxygen compounds.The example of heterocyclic radical includes, but not limited to Oxyranyle, azelidinyl, oxetanylmethoxy, sulphur Heterocycle butyl, pyrrolidinyl (such as 2- pyrrolidinyls), 2- pyrrolinyls, 3- pyrrolinyls, pyrazolidinyl, imidazolinyl, imidazoles Alkyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3- dioxy cyclopenta, two sulphur cyclopenta, four Hydrogen pyranose, dihydro pyranyl, 2H- pyranoses, 4H- pyranoses, tetrahydro thiapyran base, piperidyl (2- piperidyls, 3- piperidyls, 4- piperidyls), morpholinyl, thio-morpholinyl, (1- oxos)-thio-morpholinyl, (1,1- dioxo)-thio-morpholinyl, piperazine Base, alkyl dioxin, dithiane base, thioxane base, homopiperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, 2- Oxa- -5- azabicyclos [2.2.1] hept- 5- bases, tetrahydro pyridyl.- CH in heterocyclic radical2- group is by the reality of-C (=O)-substitution Example includes, but not limited to 2- oxo-pyrrolidine bases, oxo -1,3-thiazoles alkyl, 2- piperidone bases, 3,5- dioxy piperazine piperidinyls. The oxidized example of sulphur atom includes, but not limited to sulfolane base, 1,1- dioxothiomorpholinyl in heterocyclic radical.It is described miscellaneous Cyclic groups are optionally substituted by one or more substituents described in the invention.When the structure clearly needs linker During group, it is interpreted as linking group for the Markush variable cited by the group.If for example, the structure needs linking group And " heterocyclic radical " is listed for the Markush group definition of the variable, then it should be understood that being somebody's turn to do " heterocyclic radical " represents connection Sub- heterocyclyl groups.
In one embodiment, heterocyclic radical is 4 molecular heterocyclic radicals of original；4 described molecular heterocyclic radicals of original Group is optionally substituted by one or more substituents described in the invention.In wherein some embodiments, 4 atom groups Into heterocyclyl groups be sub- heterocyclyl groups, including but not limited toEtc..
In another embodiment, heterocyclic radical is 5 molecular heterocyclic radicals of original；The described molecular heterocyclic radical base of 5 originals Group is optionally substituted by one or more substituents described in the invention.In wherein some embodiments, 5 originals are molecular miscellaneous Cyclic groups are sub- heterocyclyl groups, including but not limited to Etc..
In another embodiment, heterocyclic radical is 6 molecular heterocyclic radicals of original；6 described molecular heterocyclyl groups of original Optionally substituted by one or more substituents described in the invention.In wherein some embodiments, 6 molecular heterocycles of original Base group is sub- heterocyclyl groups, including but not limited to Etc..
Also in one embodiment, heterocyclic radical is 7-12 former molecular heterocyclic radical；The former molecular heterocycle of described 7-12 Base group is optionally substituted by one or more substituents described in the invention.In wherein some embodiments, 7-12 atom composition Heterocyclyl groups be sub- heterocyclyl groups, including but not limited to Etc..
Term " cycloheteroalkylalkyl " refers to that alkyl group is substituted by one or more heterocyclyl groups；Wherein heterocyclic radical and alkane Base group has implication as described in the present invention.
Term " heterocyclylalkoxy " refers to that alkoxy base is substituted by one or more heterocyclyl groups；Wherein heterocyclic radical There is implication as described in the present invention with alkoxy base.
Term " heterocyclylamino group " refers to that amino group is substituted by one or two heterocyclyl groups；Wherein heterocyclyl groups With implication as described in the present invention.
Term " heterocyclic radical epoxide " refers to the heterocyclic radical optionally substituted, as defined herein, is connected on oxygen atom, And it is connected by oxygen atom with molecule remainder, wherein heterocyclyl groups have implication as described in the present invention.
Term " heterocyclyloxyalkyl " refers to that alkyl group is substituted by one or more heterocyclic radical epoxide groups；It is wherein miscellaneous Ring group epoxide and alkyl group have implication as described in the present invention.
Term " n1Individual original is molecular ", wherein n1It is integer, typically describes the number of ring member nitrogen atoms in molecule, in institute The number for stating ring member nitrogen atoms in molecule is n1.For example, piperidyl is 6 molecular Heterocyclylalkyls of original.
Used term is " undersaturated " in the present invention represents to contain one or more degrees of unsaturation in group.
Term " hetero atom " refers to O, S, N, P and Si, includes the form of any oxidation state of N, S and P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the form that the hydrogen in heterocycle on nitrogen-atoms is substituted, for example, N is (as in 3,4- dihydro-2 h-pyrrole bases N), NH (as the NH in pyrrolidinyl) or NR (NR in the pyrrolidinyl substituted as N-).
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " aryl " represents to contain 6-14 annular atom, or 6-12 annular atom, or 6-10 annular atom is monocyclic, double The carbocyclic ring system of ring and three rings, wherein, at least one member ring systems are aromatic, and each of which member ring systems include 3-7 original Molecular ring, and there are one or more attachment points to be connected with the remainder of molecule.Term " aryl " can be with term " fragrance Ring ", which exchanges, to be used.The example of aromatic yl group can include phenyl, indenyl, naphthyl and anthryl.The aromatic yl group is optionally by one Individual or multiple substituents described in the invention are substituted.
Term " aralkyl " represents that alkyl group is substituted by one or more aromatic yl groups；Wherein alkyl group and aryl Group has implication as described in the present invention.
Term " alkoxy aryl " represents that alkoxy base is substituted by one or more aromatic yl groups；Wherein alkoxy base Group and aromatic yl group have implication as described in the present invention.The example of alkoxy aryl includes, but not limited to benzyloxy, fluoro Benzyloxy, chloro benzyloxy, the benzyloxy of cyano group substitution, the benzyloxy, phenyl ethoxy, etc. of mesyl substitution.
Term " fragrant amino " represents by one or two aromatic yl group to be substituted by amino group；Wherein aromatic yl group has Implication as described in the present invention.
Term " aryloxy group " or " aryloxy " refer to the aryl optionally substituted, as defined herein, are connected to oxygen On atom, and it is connected by oxygen atom with molecule remainder, wherein aromatic yl group has implication as described in the present invention.Fragrant oxygen The example of base includes, but not limited to phenoxy group, halogenated phenoxy, the phenoxy group of cyano group substitution, the phenoxy group of hydroxyl substitution, etc. Deng.
Term " aryloxy alkyl " refers to that alkyl group is substituted by one or more aryloxy groups；Wherein aryloxy group and alkane Base group has implication as described in the present invention.The example of aryloxy alkyl includes, but not limited to phenoxymethyl, fluorobenzene Epoxide methyl (such as (2- fluorophenoxies) methyl, (3- fluorophenoxies) methyl or (4- fluorophenoxies) methyl), chloro phenoxy group first Base, etc..
Term " heteroaryl " represents to contain 5-12 annular atom, or 5-10 annular atom, or 5-6 annular atom it is monocyclic, Bicyclic and three-ring system, wherein at least one member ring systems are aromatic, and at least one member ring systems are comprising one or more miscellaneous Atom, each of which member ring systems include 5-7 former molecular ring, and have one or more attachment points and molecule remainder It is connected.Term " heteroaryl " can exchange use with term " hetero-aromatic ring " or " heteroaromatics ".The heteroaryl groups are appointed Selection of land is substituted by one or more substituents described in the invention.In one embodiment, 5-10 original is molecular miscellaneous Aryl includes 1,2,3 or 4 hetero atom for being independently selected from O, S and N.
The example of heteroaryl groups includes, but is not limited to, 2- furyls, 3- furyls, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- isoxazolyls, 5- isoxazolyls, 2- oxazolyls, 4- oxazolyls, 5- oxazoles Base, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- Pyrimidine radicals, pyridazinyl (such as 3- pyridazinyls), 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, tetrazole radical (such as 5- tetrazole radicals), triazole Base (such as 2- triazolyls and 5- triazolyls), 2- thienyls, 3- thienyls, pyrazolyl, isothiazolyl, 1,2,3- oxadiazolyl, 1, 2,5- oxadiazolyls, 1,2,4- oxadiazolyl, 1,2,3-triazoles base, 1,2,3- thio biphosphole base, 1,3,4- thio biphosphole base, 1, 2,5- thio biphosphole bases, pyrazinyl, 1,3,5-triazines base, pyrimidine ketone group, pyriconyl；Also include it is following bicyclic, but never It is bicyclic to be limited to these：Benzimidazolyl, benzofuranyl, benzo tetrahydrofuran base, benzothienyl, indyl (such as 2- indoles Base), etc..
In one embodiment, heteroaryl groups are following subformula：
Etc..
Term " heteroaryl alkyl " represents that alkyl group is substituted by one or more heteroaryl groups；Wherein alkyl group There is implication as described in the present invention with heteroaryl groups.Such example includes, but is not limited to, pyridine -2- ylmethyls, pyrrole Pyridine -2- base ethyls, pyridin-3-yl methyl, pyridin-4-yl methyl, pyrimidine -2-base methyl, pyrimidine -2-base ethyl, pyrimidine -2-base Propyl group, pyrimidine-4-yl methyl, pyrimidine -5- ylmethyls, thiazol-2-yl methyl, thiazole-4-yl methyl, thiazole -5- ylmethyls, miaow Azoles -2- ylmethyls, imidazoles -2- base ethyls, pyrazine -2- ylmethyls, etc..
Term " heteroarylalkoxy " represents that alkoxy base is substituted by one or more heteroaryl groups, wherein alcoxyl Base group and heteroaryl groups have implication as described in the present invention.The example of heteroarylalkoxy includes, but is not limited to, pyrrole Pyridine -2- ylmethoxies, pyridin-3-yl methoxyl group, pyridin-4-yl methoxyl group, pyrimidine -2-base methoxyl group, pyrimidine-4-yl methoxy Base, pyrimidine -5- ylmethoxies, pyrazine -2- ylmethoxies, pyridazine -3- ylmethoxies, pyridazine -4- ylmethoxies, thiazol-2-yl Methoxyl group, thiazole-4-yl methoxyl group, thiazole -5- ylmethoxies, 2- methylthiazol -5- ylmethoxies, 5- methylthiazol -2- bases Methoxyl group, etc..
Term " heteroaryl amino " represents that amino group is substituted by one or two heteroaryl groups；Wherein heteroaryl base Group has implication as described in the present invention.
Term " heteroaryl epoxide " refers to the heteroaryl optionally substituted, as defined herein, is connected on oxygen atom, And it is connected by oxygen atom with molecule remainder, wherein heteroaryl groups have implication as described in the present invention.Heteroaryl oxygen The example of base includes, but is not limited to, thiazol-2-yl epoxide, thiazole-4-yl epoxide, thiazole -5- base epoxides, etc..
Term " heteroaryl epoxide alkyl " refers to that alkyl group is substituted by one or more heteroaryl epoxide groups, wherein miscellaneous Aryloxy and alkyl group have implication as described in the present invention.
When term " blocking group " or " PG " refer to a substituent with other reacted with functional groups, commonly used to hinder It is disconnected or protect special feature.For example, " blocking group of amino " refers to that a substituent is connected with amino group to block Or the feature of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl Substituent be used for blocking or protecting the feature of hydroxyl, suitable blocking group includes acetyl group and silicyl." carboxyl is protected Shield group " refers to that the substituent of carboxyl is used for blocking or protect the feature of carboxyl, in general carboxyl-protecting group includes- CH2CH2SO2Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The description of group in general refers to document：T W.Greene,Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005。
Term " prodrug " used in the present invention, represent a compound and be converted into formula (I), formula (II), formula in vivo (IIa), the compound shown in formula (III), formula (IIIa), formula (IIIb), formula (IIIc) or formula (IV).Such conversion is by precursor Medicine hydrolyzes in blood or the influence in blood or tissue through enzymatic conversion for precursor structure.Precursor medicine species chemical combination of the present invention Thing can be ester, and ester can be as the phenyl ester class that has of pro-drug, aliphatic (C in existing invention1-24) esters, acyloxy Methyl esters, carbonic ester, carbamates and amino acid esters.Such as a compound in the present invention includes hydroxyl, i.e., It can be acylated to obtain the compound of prodrug form.Other prodrug forms include phosphate, such as these phosphoric acid Ester type compound is obtained through the di on parent.Completely discuss and may be referred to hereafter on pro-drug Offer：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified that its activity can be retouched by such as the present invention by technology known to art Adopt as stating and experimentally characterized.Such product can be by, by aoxidizing, being reduced, water to drug compound The methods of solution, amidated, desamido- effect, esterification, degreasing, enzymatic lysis etc., obtains.Correspondingly, the present invention includes compound Metabolite, including by the present invention compound metabolite caused by a period of time is fully contacted with mammal.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compounds of this invention.Term " pharmaceutically acceptable " material or the composition of including must be adapted to chemistry or toxicologically, the other components with forming preparation It is relevant with the mammal for treatment.Pharmaceutically acceptable salt is known to us in art, such as document： S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:It is 1-19. described.The type of pharmaceutically acceptable salt is included but not It is limited to：(1) acid-addition salts：By the way that the free alkali form of compound and pharmaceutically acceptable inorganic acid reaction are formed, the nothing Machine acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid；Or formed with organic acid reaction, it is described organic Acid as acetic acid, trifluoroacetic acid, hydroxyacetic acid, propionic acid, caproic acid, stearic acid, pentamethylene propionic acid, pyruvic acid, lactic acid, lactobionic acid, Malonic acid, butanedioic acid, malic acid, maleic acid, hippuric acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4- hydroxyls Benzoyl) benzoic acid, cinnamic acid, mandelic acid, Loprazolam, ethane sulfonic acid, 1,2- ethionic acids, 2- ethylenehydrinsulfonic acids, benzene Sulfonic acid, toluenesulfonic acid, 2- naphthalene sulfonic acids, 4- methyl bicycles-[2.2.2] oct-2-ene -1- formic acid, glucoheptonic acid, 4,4 '-methylene Double-(3- hydroxyl -2- alkene -1- formic acid), 3- phenylpropionic acids, trimethylace tonitric, butylacetic acid, dodecyl sulphate, gluconic acid, Glutamic acid, hydroxynaphthoic acid, salicylic acid, sulfosalicylic acid, stearic acid, muconic acid, nicotinic acid, palmitic acid etc.；(2) base addition salts, its Acid proton in parent compound is formed when being replaced by metal ion, such as alkali metal ion (such as lithium, sodium, potassium), alkali Earthmetal cations (such as magnesium or calcium) or aluminium ion；Or it is coordinated with organic base.In certain embodiments, the salt derived from sodium, Potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt includes ammonium, potassium, sodium, calcium and magnesium salts.Acceptable organic base includes Primary amine, secondary amine and tertiary amine, substituted amine includes naturally occurring substituted amine, cyclic amine, deacidite etc., such as different Propylamine, diethylamine, monoethanolamine, diethanol amine, triethanolamine, trimethylamine, N- methyl glucoses osamine, tardocillin (benzathine), choline salt (cholinate), lysine, meglumine (meglumine), piperazine, tromethamine, etc..Can The inorganic base of receiving includes aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide etc..
The officinal salt of the present invention can be synthesized with conventional chemical processes by parent compound, alkalescence or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate etc.) reaction, or by making the free alkali form and chemistry of these compounds It is prepared by the suitable acid reaction of metered amount.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, in appropriate cases, it is necessary to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton,Pa.,1985；" pharmaceutical salts handbook：Property, selection and application (Handbook of Pharmaceutical Salts:Properties, Selection and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list of the suitable salt of other can be found in.
" solvate " of the present invention refers to the association that the compound of one or more solvent molecules and the present invention are formed Thing.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated matter that water is formed.
Any disease of term " treatment " or illness as used in the present invention, in some of these embodiments, " treatment " Refer to improve disease or illness (slow down or prevent mitigate disease or the development of its at least one clinical symptoms).In other realities Apply in scheme, " treatment " refers to mitigation or improve at least one body parameter, including the body parameter that may not be discovered by patient. In other embodiments, " treatment " refers to from body (such as stablizing perceptible symptom) or physiologically (such as stable The parameter of body) or above-mentioned two aspects regulation disease or illness.In other embodiments, " treatment " refers to prevention or delay disease Breaking-out, generation or the deterioration of disease or illness.
" inflammatory disease " used in the present invention refers to the excessive inflammation caused by excessive or out of control inflammatory responses Property symptom, host tissue infringement or function of organization any disease for losing, disorderly or symptom." inflammatory disease " also refers to by leucocyte Inflow and/or the pathologic state of Neutrophil chemotaxis mediation.
" inflammation " used in the present invention refers to that the topical protective as caused by tissue damaged or destruction responds, and it is used to break Tissue that is bad, diluting or separate (isolation) harmful material and be damaged.Inflammation is flowed into leucocyte and/or neutrophil cell becomes The property changed has significant contact.Inflammation can result from the infection of pathogenic organism and virus and non-infectious mode, such as heart Wound or Reperfu- sion after muscle infarction or apoplexy, to the immune response and autoimmune response of exotic antigen.Therefore, this can be used The inflammatory disease of disclosure of the invention compounds for treating includes：Reacted with the reaction of specific system of defense and non-specific defense system Related disease.
" autoimmune disease " used in the present invention or " autoimmune disease " refer to and body fluid or cell-mediated The set of any disease of the tissue damage related to the response of body itself component.The example of autoimmune disease includes lupus, Multiple sclerosis, muscle contracting lateral sclerosis, rheumatoid arthritis, psoriasis, type i diabetes, caused by organ transplant Complication, foreign matter transplanting, diabetes, cancer, asthma, atopic dermatitis, AITD, ulcerative colitis, Crohn disease, Alzheimer disease, leukaemia and lymthoma.
As used in the present invention " arthritis disease " refer to be to be attributable to various etiologic etiological arthritis damages Any disease of feature." dermatitis " refers to characterized by being attributable to various etiologic etiological scytitises as used in the present invention Disease of skin extended familys in any one." graft rejection " refers to transplanting or surrounding tissue as used in the present invention Function forfeiture, pain, swelling, leukocytosis and decrease of platelet be characterized confrontation transplanting tissue, such as organ or cell Any immune response of (such as marrow).The treatment method of the present invention includes being used to treat the disease related to inflammatory cell activation Method.
Term " cancer " and " cancer " refer to or described the physiology in patient generally characterized by cell growth out of control Illness." tumour " includes one or more cancer cells.The example of cancer includes but is not limited to cancer (carcinoma), lymthoma, embryo Cytoma, sarcoma and leukaemia, or malignant lymph proliferative disease (lymphoid malignancies).Such cancer is more Specific example includes squamous cell carcinoma (such as epithelium squamous cell carcinoma), lung cancer (including ED-SCLC, non-small cell lung cancer (NSCLC), adenocarcinoma of lung and lung carcinoma squamosum), peritoneal cancer, hepatocellular carcinoma (hepatocellular cancer), stomach cancer (gastric Or stomach cancer) (including human primary gastrointestinal cancers), cancer of pancreas, glioblastoma, cervical carcinoma, oophoroma, liver cancer (liver Cancer), carcinoma of urinary bladder, hepatoma (hepatoma), breast cancer, colon and rectum carcinoma, colorectal cancer, carcinoma of endometrium or Uterine cancer, salivary-gland carcinoma, kidney or renal cancer (kidney or renal cancer), prostate cancer, carcinoma of vulva, thyroid gland Cancer, liver cancer (hepatic carcinoma), cancer of anus, carcinoma of penis and head and neck cancer.
The description of the compounds of this invention
Treatment of the compound and its pharmaceutical composition of the present invention to autoimmune disease or cancer has potential effect.
On the one hand, the present invention relates to a kind of heteroaryl compound or its stereoisomer, geometric isomer, dynamic isomer, Raceme, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug.
On the one hand, the present invention relates to a kind of compound, it is compound shown in the compound or formula (I) as shown in formula (I) Stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically may be used The salt or prodrug of receiving：
Wherein：
I) X is alkylidene or sub- miscellaneous alkyl；
X is optionally by 1,2,3,4,5,6,7,8,9,10,11,12,13 or 14 RXSubstituted；
Each RXIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), alkane Base, alkenyl, alkynyl, alkoxy or alkylamino；
Ay is hydroxyl, alkoxy, alkoxyalkyl or Cy1；Ay is optionally by 1,2,3,4,5,6,7,8,9 or 10 substitution Base is substituted, and the substituent is selected from RA1、RA2、RA3、RA4、RA5Or RA6；
Wherein Cy1 is cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl or heteroaryl；
Each RA1、RA2、RA3、RA4、RA5And RA6Independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, aldehyde radical, oxo (=O) ,-C (=O)-NRcRd,-S (=O)2-NRcRd, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, Haloalkyl, halogenated alkoxy, alkoxyalkyl, alkyl amino alkyl, the alkyl of cyano group substitution, alkoxy, the cyanogen of cyano group substitution The alkylamino of base substitution, the alkyl of hydroxyl substitution, the alkoxy of hydroxyl substitution, alkylamino, cycloalkyl, the cyclenes of hydroxyl substitution Base, heterocyclic radical, aryl, heteroaryl, cycloalkyl-alkyl, cycloalkenyl alkyl, cycloheteroalkylalkyl, aralkyl, heteroaryl alkyl, cycloalkanes Base amino, cycloalkenyl group amino, heterocyclylamino group, fragrant amino, heteroaryl amino, cycloalkyl oxy, cycloalkenyl oxy, heterocyclyloxy Base, aryloxy group, heteroaryl epoxide, cycloalkyloxyalkyl, cycloalkenyl oxy alkyl, heterocyclyloxyalkyl, aryloxy alkyl, Heteroaryl epoxide alkyl, cycloalkyl alkoxy, cycloalkenyl group alkoxy, heterocyclylalkoxy, alkoxy aryl or heteroarylalkoxy Base；Each RA1、RA2、RA3、RA4、RA5And RA6Individually optionally by 1,2,3,4,5 or 6 R1Substituted；
Z is-(CRjRm)s-Hy-RBOr-(CReRf)m-NRgRB1；
Wherein Hy is cycloalkylidene, sub- cycloalkenyl group, sub- heterocyclic radical, arlydene or inferior heteroaryl；
Each Re、Rf、RjAnd RmIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), alkyl, alkenyl or alkynyl；
M is 1,2,3,4,5 or 6；
S is 0,1,2,3,4,5 or 6；
RgFor hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, cycloalkyl-alkyl, ring Alkenylalkyl, cycloheteroalkylalkyl ,-C (=O)-aryl ,-C (=O)-heteroaryl, aralkyl or heteroaryl alkyl；
RBThe alkyl substituted for cyano group or cyano group；Or RBFor following subformula：
Each RB1It independently is hydrogen or the alkyl of cyano group substitution；Or each RB1It independently is following subformula：
Each Ry1、Ry2、Ry4And Ry3It independently is hydrogen, halogen, methyl or cyano group；
Cy3 is cycloalkylidene, sub- cycloalkenyl group, sub- heterocyclic radical, arlydene or inferior heteroaryl；
RnFor hydrogen, alkyl, haloalkyl, cycloalkyl or halogenated cycloalkyl；
Each R3、R3a、R6、R9、R12、R15、R20And R23It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, carboxyl or alkyl；
Each R4、R3b、R5、R7、R8、R10、R11、R13、R14、R16、R17、R21、R22、R24And R25Independently be hydrogen, deuterium, fluorine, chlorine, Bromine, iodine, cyano group, carboxyl ,-(CRiRk)n-NRvRw, alkyl, haloalkyl, hydroxyl substitution alkyl, alkenyl, alkynyl, alkoxy alkane Base, alkyl amino alkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclic radical, cycloheteroalkylalkyl, aryl, aryl alkyl, heteroaryl or heteroaryl Base alkyl；
Each R18、R19And R26It independently is hydrogen, deuterium, alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, alkylamino alkane Base, cycloalkyl, cycloalkyl-alkyl, cycloheteroalkylalkyl, aryl alkyl or heteroaryl alkyl；
Each R27、R28、R29And R30It independently is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, alkylamino alkane Base, cycloalkyl, cycloalkyl-alkyl, cycloheteroalkylalkyl, aryl alkyl or heteroaryl alkyl；
Each k independently is 0,1,2,3 or 4；
Each RiAnd RkIndependently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), Alkyl, alkenyl or alkynyl；
N is 1,2,3,4,5 or 6；
Each R3c、R3d、RvAnd RwIt independently is H, deuterium, alkyl, alkyl, haloalkyl, alkoxyalkyl, the ring of cyano group substitution Alkyl, aryl, heteroaryl, heterocyclic radical or cycloheteroalkylalkyl；Or Rv、RwFormed together with the N atoms being attached thereto former by 3-12 Molecular heterocycle；
Ii) X is a key；
Z is
Ay is Cy2；Wherein Cy2 is cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl or heteroaryl；Cy2 is optionally by 1,2,3, 4th, 5,6,7,8,9 or 10 substituents are substituted, and the substituent is selected from RA7、RA8、RA9、RA10Or RA11；
Each RA7、RA8、RA9、RA10And RA11It independently is H, deuterium, halogen, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), alkyl, C2-10Alkoxy, alkylamino, haloalkyl, halogenated alkoxy, the alkyl of hydroxyl substitution, the alkane of hydroxyl substitution Epoxide, the alkyl of cyano group substitution, alkoxy, alkyloxy-alkoxy, the-(CR of cyano group substitutionaRb)z- C (=O)-NRcRd, cycloalkanes It is base, heterocyclic radical, aryl, heteroaryl, cycloalkyl-alkyl, cycloheteroalkylalkyl, aryl alkyl, heteroaryl alkyl, cycloalkyl oxy, miscellaneous Ring group epoxide, aryloxy group, heteroaryl epoxide, cycloalkyl alkoxy, heterocyclylalkoxy, alkoxy aryl or heteroarylalkoxy Base；Each RA7、RA8、RA9、RA10And RA11Individually optionally by 1,2,3,4,5 or 6 R1xSubstituted；
Z is 0,1,2 or 3；
Each RaAnd RbIt independently is hydrogen, deuterium, halogen, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), alkyl, alkene Base or alkynyl；
Each RcAnd RdIt independently is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, ring Alkyl-alkyl, cycloalkenyl alkyl, cycloheteroalkylalkyl, aralkyl or heteroaryl alkyl；Each RcAnd RdIndividually optionally by 1,2,3,4, 5 or 6 R2Substituted；
Each R2It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), alkane Base, haloalkyl, the alkyl of hydroxyl substitution, alkyl, alkenyl, alkynyl, alkoxy or the alkylamino of cyano group substitution；
Each R1And R1xIndependently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), Alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkyl sulphonyl, haloalkyl, halogenated alkoxy, alkoxyalkyl, alkylamino Alkyl, the alkyl of cyano group substitution, the alkoxy of cyano group substitution, the alkylamino of cyano group substitution, the alkyl of hydroxyl substitution, hydroxyl substitution Alkoxy or hydroxyl substitution alkylamino；With
Each X, RX、Ay、Cy1、Cy2、Cy3、RA1、RA2、RA3、RA4、RA5、RA6、RA7、RA8、RA9、RA10、RA11、Ra、Rb、R1、 Rc、Rd、R2、Hy、RB、RB1、Re、Rf、Rg、Rj、Rm、Rn、R3、R3a、R3b、R3c、R3d、R4、R5、R6、R7、R8、R9、R10、R11、R12、 R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、R28、R29、R30、Ri、Rk、RvAnd RwIt is independent to appoint Selection of land is substituted by 1,2,3,4,5,6,7,8,9 or 10 substituent, and the substituent is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyanogen Base, hydroxyl, nitro, amino, carboxyl, oxo (=O), alkyl, alkoxy, alkoxyalkyl, alkyl-C (=O)-, cyano group substitution Alkyl-C (=O)-, alkylamino, NH2- S (=O)2-, alkyl-NH-S (=O)2-、NH2- S (=O)2- alkyl, haloalkyl, Alkyl, alkyl, cycloalkyl, heterocyclic radical, aryl, aryloxy group or the alkoxy aryl of cyano group substitution of hydroxyl substitution.
Some of embodiments are each X, RX、Ay、Cy1、Cy2、Cy3、RA1、RA2、RA3、RA4、RA5、RA6、RA7、RA8、 RA9、RA10、RA11、Ra、Rb、R1、Rc、Rd、R2、Hy、RB、RB1、Re、Rf、Rg、Rj、Rm、Rn、R3、R3a、R3b、R3c、R3d、R4、R5、R6、 R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、R28、R29、 R30、Ri、Rk、RvAnd RwSubstituted individually optionally by 1,2,3,4,5,6,7,8,9 or 10 substituent, the substituent is selected from Hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), C1-6Alkyl, C1-6Alkoxy, C1-6Alkane Epoxide C1-6Alkyl, C1-6Alkyl-C (=O)-, cyano group substitution C1-6Alkyl-C (=O)-, C1-6Alkylamino, NH2- S (=O)2-、 C1-6Alkyl-NH-S (=O)2-、NH2- S (=O)2-C1-6Alkyl, halo C1-6Alkyl, the C of hydroxyl substitution1-6Alkyl, cyano group substitution C1-6Alkyl, C3-6Cycloalkyl, C2-8Heterocyclic radical, C6-10Aryl, C6-10Aryloxy group or C6-10Aryl C1-6Alkoxy.
Some of embodiments are that the present invention relates to a kind of compound, and it is the compound or formula as shown in formula (II) (II) stereoisomer, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, the solvent of compound shown in Compound, metabolite and pharmaceutically acceptable salt or prodrug：
Wherein：
X is alkylidene or sub- miscellaneous alkyl；X is optionally by 1,2,3,4,5,6,7,8,9,10,11,12,13 or 14 RXInstitute Substitution；
Wherein RX, Cy1, s, Hy and RBWith implication as described in the present invention.
Fig. 4 (IIa) stereoisomer, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, the solvent of compound shown in Compound, metabolite and pharmaceutically acceptable salt or prodrug：
Wherein：
X is alkylidene or sub- miscellaneous alkyl；X is optionally by 1,2,3,4,5,6,7,8,9,10,11,12,13 or 14 RXInstitute Substitution；
Wherein RX, Cy1 there is implication as described in the present invention.
Some of embodiments are that the present invention relates to a kind of compound, and it is the compound or formula as shown in formula (III) (III) stereoisomer, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, the solvent of compound shown in Compound, metabolite and pharmaceutically acceptable salt or prodrug：
Wherein：
Cy2 has implication as described in the present invention.
Some of embodiments are that Ay is hydroxyl, C1-3Alkoxy, C1-3Alkoxy C1-4Alkyl or Cy1；Wherein Cy1 is C3-8Cycloalkyl, C3-8Cycloalkenyl group, C2-10Heterocyclic radical, C6-10Aryl or C1-9Heteroaryl；Cy1 is optionally by 1,2,3,4,5,6,7,8, 9 or 10 substituents are substituted, and the substituent is selected from RA1、RA2、RA3、RA4、RA5Or RA6；
Wherein RA1、RA2、RA3、RA4、RA5And RA6With implication as described in the present invention.
Some of embodiments are Cy2 C3-8Cycloalkyl, C3-8Cycloalkenyl group, C2-10Heterocyclic radical, C6-10Aryl or C1-9It is miscellaneous Aryl；Cy2 is optionally substituted by 1,2,3,4,5,6,7,8,9 or 10 substituent, and the substituent is selected from RA7、RA8、RA9、 RA10Or RA11；
Wherein RA7、RA8、RA9、RA10And RA11With implication as described in the present invention.
Some of embodiments are that Cy1 and Cy2 are each independently C3-6Cycloalkyl, C3-6Cycloalkenyl group, C2-8Heterocyclic radical, C6-10Aryl or C1-9Heteroaryl；Cy1 is optionally substituted by 1,2,3,4,5,6,7,8,9 or 10 substituent, the substituent Selected from RA1、RA2、RA3、RA4、RA5Or RA6；Cy2 is optionally substituted by 1,2,3,4,5,6,7,8,9 or 10 substituent, described Substituent is selected from RA7、RA8、RA9、RA10Or RA11；
Wherein RA1、RA2、RA3、RA4、RA5、RA6、RA7、RA8、RA9、RA10And RA11With implication as described in the present invention.
Some of embodiments are that Cy1 and Cy2 are each independently cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, ring Cyclobutenyl, cyclopentenyl, cyclopentadienyl group, cyclohexenyl group, cyclohexadienyl, piperidyl, piperazinyl, morpholinyl, thiomorpholine Base, 1- oxos thio-morpholinyl, 1,1- dioxothiomorpholinyls or iso-indoles -1,3- diketone -4- bases；Cy1 optionally by 1, 2nd, 3,4,5,6,7,8,9 or 10 substituents are substituted, and the substituent is selected from RA1、RA2、RA3、RA4、RA5Or RA6；Cy2 is optional Ground is substituted by 1,2,3,4,5,6,7,8,9 or 10 substituent, and the substituent is selected from RA7、RA8、RA9、RA10Or RA11；
Wherein RA1、RA2、RA3、RA4、RA5、RA6、RA7、RA8、RA9、RA10And RA11With implication as described in the present invention.
Some of embodiments are that Cy1 and Cy2 are each independently following subformula：
Cy1 is optionally substituted by 1,2,3,4,5,6,7,8,9 or 10 substituent, and the substituent is selected from RA1、RA2、RA3、RA4、RA5Or RA6；Cy2 is optionally substituted by 1,2,3,4,5,6,7,8,9 or 10 substituent, the substitution Base is selected from RA7、RA8、RA9、RA10Or RA11；
Wherein RA1、RA2、RA3、RA4、RA5、RA6、RA7、RA8、RA9、RA10And RA11With implication as described in the present invention.
Some of embodiments are that Z is-(CRjRm)s-Hy-RBOr-(CReRf)m-NRgRB1；
Wherein Rj、Rm、s、Hy、RB、Re、Rf、m、RgAnd RB1With implication as described in the present invention.
Some of embodiments are Hy C3-8Cycloalkylidene, C3-8Sub- cycloalkenyl group, C2-15Sub- heterocyclic radical, C6-10Arlydene Or C1-9Inferior heteroaryl.
Some of embodiments are each Re、Rf、RjAnd RmIndependently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, Nitro, amino, carboxyl, oxo (=O), C1-3Alkyl, C2-4Alkenyl or C2-4Alkynyl.
Some of embodiments are RgFor hydrogen, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-6Cycloalkyl, C3-6Cyclenes Base, C2-8Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C3-6Cycloalkyl C1-6Alkyl, C3-6Cycloalkenyl group C1-6Alkyl, C2-8Heterocyclic radical C1-6Alkyl ,-C (=O)-C6-10Aryl ,-C (=O)-C1-9Heteroaryl, C6-10Aryl C1-6Alkyl or C1-9Heteroaryl C1-6Alkyl.
Some of embodiments are Hy C3-6Cycloalkylidene, C3-6Sub- cycloalkenyl group, C6-10Arlydene or C1-6Sub- heteroaryl Base.
Some of embodiments are that Hy is following subformula：
Wherein：
For-or=；
Each p1And p2It independently is 0,1 or 2；
Each q1And q2It independently is 0,1,2 or 3；
s1For 1,2,3 or 4；
s2For 1,2 or 3；
Each q3And q4It independently is 0,1,2 or 3；With
Each s3And s4It independently is 0,1,2 or 3.
Some of embodiments are that Hy is following subformula：
Other embodiment is that Z is following subformula：
Wherein：For-or=；
Rj、Rm、s、p1、p2、q1、q2、q3、q4、s1、s2、s3、s4And RBWith implication as described in the present invention.
Other embodiment is that Z is following subformula：
Wherein RBWith implication as described in the present invention.
Other embodiment is-Hy-RBFor following subformula：
Wherein：For-or=；
Each p1、p2、q1、q2、q3、q4、s1、s2、s3、s4And RBWith implication as described in the present invention.
Other embodiment is-Hy-RBFor following subformula：
Wherein RBWith as described herein Implication.
Some of embodiments are RBThe C substituted for cyano group or cyano group1-4Alkyl.
Some of embodiments are each RB1It independently is hydrogen or the C of cyano group substitution1-4Alkyl.
Some of embodiments are RBFor following subformula：
Each RB1It independently is following subformula：
Wherein R3、R3a、R3b、R3c、R3d、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、 R20、R21、R22、R23、R24、R25、R26、R27、R28、R29、R30、Ry1、Ry2、Ry3、Ry4、Cy3、Rn, k have it is as described in the present invention Implication.
Some of embodiments are each Ry1、Ry2、Ry4And Ry3It independently is hydrogen, halogen, methyl or cyano group.
Some of embodiments are Cy3 C3-6Cycloalkylidene, C3-6Sub- cycloalkenyl group, C2-6Sub- heterocyclic radical, C6-10Sub- virtue Base or C1-6Inferior heteroaryl.
Some of embodiments are RnFor hydrogen, C1-3Alkyl, halo C1-3Alkyl, C3-6Cycloalkyl or halo C3-6Cycloalkanes Base.
Some of embodiments are each R3、R3a、R6、R9、R12、R15、R20And R23Independently be hydrogen, deuterium, fluorine, chlorine, bromine, Iodine, cyano group, carboxyl or C1-3Alkyl.
Some of embodiments are each R4、R3b、R5、R7、R8、R10、R11、R13、R14、R16、R17、R21、R22、R24And R25 It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, carboxyl ,-(CRiRk)n-NRvRw、C1-3Alkyl, halo C1-3Alkyl, hydroxyl take The C in generation1-3Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Alkoxy C1-4Alkyl, C1-3Alkylamino C1-3Alkyl, C3-6Cycloalkyl, C3-6Ring Alkyl C1-3Alkyl, C2-6Heterocyclic radical, C2-6Heterocyclic radical C1-3Alkyl, C6-10Aryl, C6-10Aryl C1-3Alkyl, C1-6Heteroaryl or C1-6 Heteroaryl C1-3Alkyl；
Wherein Ri、Rk、n、RvAnd RwWith implication as described in the present invention.
Some of embodiments are each R18、R19And R26It independently is hydrogen, deuterium, C1-4Alkyl, halo C1-3Alkyl, C2-4 Alkenyl, C2-4Alkynyl, C1-3Alkoxy C1-3Alkyl, C1-3Alkylamino C1-3Alkyl, C3-6Cycloalkyl, C3-6Cycloalkyl C1-3Alkyl, C2-6 Heterocyclic radical C1-3Alkyl, C6-10Aryl C1-3Alkyl or C1-6Heteroaryl C1-3Alkyl.
Some of embodiments are each R27、R28、R29And R30It independently is hydrogen, C1-4Alkyl, halo C1-4Alkyl, C2-4 Alkenyl, C2-4Alkynyl, C1-3Alkoxy C1-3Alkyl, C1-3Alkylamino C1-3Alkyl, C3-6Cycloalkyl, C3-6Cycloalkyl C1-3Alkyl, C2-6 Heterocyclic radical C1-3Alkyl, C6-10Aryl C1-3Alkyl or C1-6Heteroaryl C1-3Alkyl.
Some of embodiments are that each k independently is 0,1,2,3 or 4.
Some of embodiments are each RiAnd RkIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, ammonia Base, carboxyl, oxo (=O), C1-3Alkyl, C2-4Alkenyl or C2-4Alkynyl.
Some of embodiments are n 1,2,3,4,5 or 6.
Some of embodiments are each R3c、R3d、RvAnd RwIt independently is hydrogen, deuterium, C1-4Alkyl, the C of cyano group substitution1-3 Alkyl, halo C1-3Alkyl, C1-3Alkoxy C1-3Alkyl, C3-6Cycloalkyl, C6-10Aryl, C1-6Heteroaryl, C2-6Heterocyclic radical or C2-6 Heterocyclic radical C1-3Alkyl.
Some of embodiments are Rv、RwFormed together with the N atoms being attached thereto former molecular miscellaneous by 3-8 Ring.
Some of embodiments are Rv、RwFormed together with the N atoms being attached thereto azelidinyl, pyrrolidinyl, Piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, 1- oxos thio-morpholinyl, 1,1- dioxothiomorpholinyls, high piperidines Base, homopiperazine base or high morpholinyl.
Some of embodiments are RBFor following subformula：
Some of embodiments are that the present invention relates to a kind of compound, and it is the compound or formula as shown in formula (IV) (IV) stereoisomer, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, the solvent of compound shown in Compound, metabolite and pharmaceutically acceptable salt or prodrug：
Wherein：
X is alkylidene or sub- miscellaneous alkyl；X is optionally by 1,2,3,4,5,6,7,8,9,10,11,12,13 or 14 RXInstitute Substitution；
Y1For N or CRA1；
Y2For N or CRA2；
Y3For N, CRA3Or CRA6；
Wherein RX、RA1、RA2、RA3、RA4、RA5And RA6With implication as described in the present invention.
Some of embodiments are X C1-8Alkylidene or C1-8Sub- miscellaneous alkyl；X is optionally by 1,2,3,4,5,6,7, 8th, 9,10,11,12,13 or 14 RXSubstituted；
Wherein RXWith implication as described in the present invention.
Some of embodiments are each RXIndependently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, oxo (=O), C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Alkoxy or C1-6Alkylamino.
Some of embodiments are that X is-(CR31R32)r-、-(CR31R32)r-O-(CR33R34)t-、-(CR31R32)r-C (=O)-(CR33R34)t-、-(CR31R32)r- S (=O)2-(CR33R34)t-、-(CR31R32)r-N(R35)-(CR33R34)t- ,-C (= O)-N(R35)-(CR33R34)t-、-(CR31R32)r-N(R35)-C (=O)-or-(CR31R32)r-N(R35)-S (=O)2-；
Each r independently is 1,2,3 or 4；
Each t independently is 0,1,2 or 3；
Each R31、R32、R33And R34It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxygen Generation (=O), C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-3Alkoxy or C1-3Alkylamino；With
Each R35It independently is hydrogen, deuterium, C1-4Alkyl, C2-4Alkenyl or C2-4Alkynyl.
Some of embodiments are that X is-CH2-、-(CH2)2-、-(CH2)3-、-C(CH3)2-、-CH2-C(CH3)2-、-C (CH3)(OH)-、-CH2-O-、-CH2-O-CH2-、-C(CH3)2-O-、-C(CH3)(OH)-O-、-CH(CH3)-O-CH2-、-C (CH3)2-O-CH2-、-CH2-NH-、-CH2-NH-CH2-、-C(CH3)2-NH-、-CH(CH3)-NH-CH2-、-C(CH3)2-NH- CH2-、-C(CH3) (OH)-NH- ,-C (=O)-NH- ,-C (=O)-NH-CH2-、-CH2- NH-C (=O)-,-CH2- NH-S (= O)2-、-(CH2)2- NH-S (=O)2-、-CH(CH3)-NH-S (=O)2- or-C (CH3)2- NH-S (=O)2-。
Some of embodiments are each RA1、RA2、RA3、RA4、RA5And RA6It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyanogen Base, hydroxyl, nitro, amino, carboxyl, aldehyde radical, oxo (=O) ,-C (=O)-NRcRd,-S (=O)2-NRcRd、C1-6Alkyl, C2-6 Alkenyl, C2-6Alkynyl, C1-6Alkoxy, C1-6Alkylamino, halo C1-6Alkyl, halo C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, the C of cyano group substitution1-6Alkyl, the C of cyano group substitution1-6Alkoxy, the C of cyano group substitution1-6Alkylamino, hydroxyl The C of base substitution1-6Alkyl, the C of hydroxyl substitution1-6Alkoxy, the C of hydroxyl substitution1-6Alkylamino, C3-6Cycloalkyl, C3-6Cycloalkenyl group, C2-8Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C3-6Cycloalkyl C1-6Alkyl, C3-6Cycloalkenyl group C1-6Alkyl, C2-8Heterocyclic radical C1-6Alkane Base, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C3-6Cycloalkyl amino, C3-6Cycloalkenyl group amino, C2-8Heterocyclic radical ammonia Base, C6-10Fragrant amino, C1-9Heteroaryl amino, C3-6Cycloalkyl oxy, C3-6Cycloalkenyl oxy, C2-8Heterocyclic radical epoxide, C6-10Fragrant oxygen Base, C1-9Heteroaryl epoxide, C3-6Cycloalkyl oxy C1-6Alkyl, C3-6Cycloalkenyl oxy C1-6Alkyl, C2-8Heterocyclic radical epoxide C1-6Alkane Base, C6-10Aryloxy group C1-6Alkyl, C1-9Heteroaryl epoxide C1-6Alkyl, C3-6Cycloalkyl C1-6Alkoxy, C3-6Cycloalkenyl group C1-6Alcoxyl Base, C2-8Heterocyclic radical C1-6Alkoxy, C6-10Aryl C1-6Alkoxy or C1-9Heteroaryl C1-6Alkoxy；Each RA1、RA2、RA3、RA4、RA5 And RA6Individually optionally by 1,2,3,4,5 or 6 R1Substituted；
Wherein R1、RcAnd RdWith implication as described in the present invention.
Some of embodiments are each R1Independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, oxo (=O), C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Alkoxy, C1-6Alkylamino, C1-6Alkyl sulphonyl, halo C1-6Alkyl, halo C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, the C of cyano group substitution1-6Alkyl, cyanogen The C of base substitution1-6Alkoxy, the C of cyano group substitution1-6Alkylamino, the C of hydroxyl substitution1-6Alkyl, the C of hydroxyl substitution1-6Alkoxy or The C of hydroxyl substitution1-6Alkylamino.
Some of embodiments are each RcAnd RdIt independently is hydrogen, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkanes Base, C3-8Cycloalkenyl group, C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C3-8Cycloalkyl C1-6Alkyl, C3-8Cycloalkenyl group C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C6-10Aryl C1-6Alkyl or C1-9Heteroaryl C1-6Alkyl；Each RcAnd RdIndividually optionally by 1,2,3, 4th, 5 or 6 R2Substituted；
Wherein R2With implication as described in the present invention.
Some of embodiments are each R2Independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, oxo (=O), C1-6Alkyl, halo C1-6Alkyl, the C of hydroxyl substitution1-6Alkyl, the C of cyano group substitution1-6Alkyl, C2-6Alkene Base, C2-6Alkynyl, C1-6Alkoxy or C1-6Alkylamino.
Some of embodiments are each RA1、RA2、RA3、RA4、RA5And RA6It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyanogen Base, hydroxyl, nitro, amino, carboxyl, aldehyde radical, oxo (=O) ,-C (=O)-NRcRd,-S (=O)2-NRcRd、C1-4Alkyl, C2-4 Alkenyl, C2-4Alkynyl, C1-4Alkoxy, C1-4Alkylamino, halo C1-4Alkyl, halo C1-4Alkoxy, C1-4Alkoxy C1-4Alkyl, C1-4Alkylamino C1-4Alkyl, the C of cyano group substitution1-4Alkyl, the C of cyano group substitution1-4Alkoxy, the C of cyano group substitution1-4Alkylamino, hydroxyl The C of base substitution1-4Alkyl, the C of hydroxyl substitution1-4Alkoxy, the C of hydroxyl substitution1-4Alkylamino, C3-6Cycloalkyl, C3-6Cycloalkenyl group, C2-6Heterocyclic radical, C6-10Aryl, C1-6Heteroaryl, C3-6Cycloalkyl C1-3Alkyl, C3-6Cycloalkenyl group C1-3Alkyl, C2-6Heterocyclic radical C1-3Alkane Base, C6-10Aryl C1-3Alkyl, C1-6Heteroaryl C1-3Alkyl, C3-6Cycloalkyl amino, C3-6Cycloalkenyl group amino, C2-6Heterocyclic radical ammonia Base, C6-10Fragrant amino, C1-6Heteroaryl amino, C3-6Cycloalkyl oxy, C3-6Cycloalkenyl oxy, C2-6Heterocyclic radical epoxide, C6-10Fragrant oxygen Base, C1-6Heteroaryl epoxide, C3-6Cycloalkyl oxy C1-3Alkyl, C3-6Cycloalkenyl oxy C1-3Alkyl, C2-6Heterocyclic radical epoxide C1-3Alkane Base, C6-10Aryloxy group C1-4Alkyl, C1-6Heteroaryl epoxide C1-3Alkyl, C3-6Cycloalkyl C1-3Alkoxy, C3-6Cycloalkenyl group C1-3Alcoxyl Base, C2-6Heterocyclic radical C1-3Alkoxy, C6-10Aryl C1-4Alkoxy or C1-6Heteroaryl C1-4Alkoxy；Each RA1、RA2、RA3、RA4、RA5 And RA6Individually optionally by 1,2,3,4,5 or 6 R1Substituted；
Wherein R1、RcAnd RdWith implication as described in the present invention.
Some of embodiments are each R1Independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, oxo (=O), C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Alkoxy, C1-4Alkylamino, C1-4Alkyl sulphonyl, halo C1-4Alkyl, halo C1-4Alkoxy, C1-4Alkoxy C1-4Alkyl, C1-4Alkylamino C1-4Alkyl, the C of cyano group substitution1-4Alkyl, cyanogen The C of base substitution1-4Alkoxy, the C of cyano group substitution1-4Alkylamino, the C of hydroxyl substitution1-4Alkyl, the C of hydroxyl substitution1-4Alkoxy or The C of hydroxyl substitution1-4Alkylamino.
Some of embodiments are each RcAnd RdIt independently is hydrogen, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-6Cycloalkanes Base, C3-6Cycloalkenyl group, C2-6Heterocyclic radical, C6-10Aryl, C1-5Heteroaryl, C3-6Cycloalkyl C1-3Alkyl, C3-6Cycloalkenyl group C1-3Alkyl, C2-6Heterocyclic radical C1-3Alkyl, C6-10Aryl C1-3Alkyl or C1-5Heteroaryl C1-3Alkyl；Each RcAnd RdIndividually optionally by 1,2,3, 4th, 5 or 6 R2Substituted；
Wherein R2With implication as described in the present invention.
Some of embodiments are each R2Independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, oxo (=O), C1-3Alkyl, C2-3Alkenyl, C2-3Alkynyl, C1-3Alkoxy or C1-3Alkylamino.
Some of embodiments are each RA1、RA2、RA3、RA4、RA5And RA6It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyanogen Base, hydroxyl, nitro, amino, carboxyl, aldehyde radical, oxo (=O), Ph-NH-C (=O)-, halogen substitution Ph-NH-C (=O)-, Ph-NH-S (=O)2-, methyl, ethyl, propyl group, isopropyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, methylamino, two Methylamino, ethylamino, halo C1-3Alkyl, halo C1-3Alkoxy, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, oxa- ring fourth Base, azelidinyl, tetrahydrofuran base, pyrrolidinyl, THP trtrahydropyranyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, Phenyl, indenyl, phenoxy group, thiazol-2-yl epoxide, thiazole-4-yl epoxide, thiazole -5- bases epoxide, pyridine radicals epoxide, pyrimidine radicals Epoxide, pyrazinyl epoxide, pyridazinyl epoxide, benzyloxy, fluorinated benzyloxy, chloro benzyloxy, benzyloxy, the first sulphur of cyano group substitution Benzyloxy, phenyl ethoxy, phenoxymethyl, fluorinated phenoxy methyl, chloro phenoxymethyl, the pyridine -2- of acyl group substitution Ylmethoxy, pyridin-3-yl methoxyl group, pyridin-4-yl methoxyl group, pyrimidinylmethoxy, pyrazine ylmethoxy, pyridazinyl methoxy Base, thiazol-2-yl methoxyl group, thiazole-4-yl methoxyl group, thiazole -5- ylmethoxies, 2- methylthiazol -5- ylmethoxies or 5- Methylthiazol -2- ylmethoxies.
Some of embodiments are, the present invention relates to a kind of compound, its for the compound as shown in formula (IIIa) or The stereoisomer of compound shown in formula (IIIa), geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, Solvate, metabolite and pharmaceutically acceptable salt or prodrug：
Wherein：
X1For N and CRA7；
RA7、RA8And RA9With implication as described in the present invention.
Some of embodiments are, the present invention relates to a kind of compound, its for the compound as shown in formula (IIIb) or The stereoisomer of compound shown in formula (IIIb), geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, Solvate, metabolite and pharmaceutically acceptable salt or prodrug：
Wherein：
RA10With implication as described in the present invention.
Some of embodiments are, the present invention relates to a kind of compound, its for the compound as shown in formula (IIIc) or The stereoisomer of compound shown in formula (IIIc), geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, Solvate, metabolite and pharmaceutically acceptable salt or prodrug：
Wherein：
A is the heteroaryl of the cycloalkyl of 5-6 members, the heterocyclic radical of 5-6 members, phenyl or 5-6 members；
Y4And Z1It is each independently CH or N；
RA11With implication as described in the present invention.
Some of embodiments are,For following subformula：
Some of embodiments are each RA7、RA8、RA9、RA10And RA11It independently is H, deuterium, halogen, cyano group, hydroxyl, nitre Base, amino, carboxyl, oxo (=O), C1-6Alkyl, C2-6Alkoxy, C1-6Alkylamino, halo C1-6Alkyl, halo C1-6Alkoxy, The C of hydroxyl substitution1-6Alkyl, the C of hydroxyl substitution1-6Alkoxy, the C of cyano group substitution1-6Alkyl, the C of cyano group substitution1-6Alkoxy, C1-6Alkoxy C1-6Alkoxy ,-(CRaRb)z- C (=O)-NRcRd、C3-8Cycloalkyl, C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl Base, C3-8Cycloalkyl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C3-8Cycloalkanes Base epoxide, C2-10Heterocyclic radical epoxide, C6-10Aryloxy group, C1-9Heteroaryl epoxide, C3-8Cycloalkyl C1-6Alkoxy, C2-10Heterocyclic radical C1-6Alkoxy, C6-10Aryl C1-6Alkoxy or C1-9Heteroaryl C1-6Alkoxy；Each RA7、RA8、RA9、RA10And RA11It is individually optional Ground is by 1,2,3,4,5 or 6 R1xSubstituted；
Wherein z, Ra、Rb、Rc、RdAnd R1xWith implication as described in the present invention.
Some of embodiments are each R1xIndependently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, oxo (=O), C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Alkoxy, C1-6Alkylamino, C1-6Alkyl sulphonyl, halo C1-6Alkyl, halo C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, the C of cyano group substitution1-6Alkyl, cyanogen The C of base substitution1-6Alkoxy, the C of cyano group substitution1-6Alkylamino, the C of hydroxyl substitution1-6Alkyl, the C of hydroxyl substitution1-6Alkoxy or The C of hydroxyl substitution1-6Alkylamino.
Some of embodiments are each RaAnd RbIt independently is hydrogen, deuterium, halogen, cyano group, hydroxyl, nitro, amino, carboxylic Base, oxo (=O), C1-6Alkyl, C2-6Alkenyl or C2-6Alkynyl.
Some of embodiments are each RcAnd RdIt independently is hydrogen, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkanes Base, C3-6Cycloalkenyl group, C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C3-8Cycloalkyl C1-6Alkyl, C3-6Cycloalkenyl group C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C6-10Aryl C1-6Alkyl or C1-9Heteroaryl C1-6Alkyl；Each RcAnd RdIndividually optionally by 1,2,3, 4th, 5 or 6 R2Substituted；
Wherein R2With implication as described in the present invention.
Some of embodiments are each R2Independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, oxo (=O), C1-6Alkyl, halo C1-6Alkyl, the C of hydroxyl substitution1-6Alkyl, the C of cyano group substitution1-6Alkyl, C2-6Alkene Base, C2-6Alkynyl, C1-6Alkoxy or C1-6Alkylamino.
Some of embodiments are each RA7、RA8、RA9、RA10And RA11It independently is H, deuterium, halogen, cyano group, hydroxyl, nitre Base, amino, carboxyl, oxo (=O), C1-4Alkyl, C2-4Alkoxy, C1-4Alkylamino, halo C1-3Alkyl, halo C1-3Alkoxy, The C of hydroxyl substitution1-3Alkyl, the C of hydroxyl substitution1-3Alkoxy, the C of cyano group substitution1-3Alkyl, the C of cyano group substitution1-3Alkoxy, C1-4Alkoxy C1-4Alkoxy ,-(CH2)z- C (=O)-NRcRd、C3-6Cycloalkyl, C2-6Heterocyclic radical, C6-10Aryl, C1-6Heteroaryl, C3-6Cycloalkyl C1-3Alkyl, C2-6Heterocyclic radical C1-3Alkyl, C6-10Aryl C1-3Alkyl, C1-6Heteroaryl C1-3Alkyl, C3-6Cycloalkyl Epoxide, C2-6Heterocyclic radical epoxide, C6-10Aryloxy group, C1-6Heteroaryl epoxide, C3-6Cycloalkyl C1-3Alkoxy, C2-6Heterocyclic radical C1-3Alkane Epoxide, C6-10Aryl C1-3Alkoxy or C1-6Heteroaryl C1-3Alkoxy；Each RA7、RA8、RA9、RA10And RA11Individually optionally by 1, 2nd, 3,4,5 or 6 R1xSubstituted；
Wherein z, Rc、RdAnd R1xWith implication as described in the present invention.
Some of embodiments are each R1xIndependently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, oxo (=O), C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-3Alkoxy, C1-3Alkylamino, C1-3Alkyl sulphonyl, halo C1-4Alkyl, halo C1-3Alkoxy, C1-3Alkoxy C1-3Alkyl, C1-3Alkylamino C1-3Alkyl, the C of cyano group substitution1-3Alkyl, cyanogen The C of base substitution1-3Alkoxy, the C of cyano group substitution1-3Alkylamino, the C of hydroxyl substitution1-3Alkyl, the C of hydroxyl substitution1-3Alkoxy or The C of hydroxyl substitution1-3Alkylamino.
Some of embodiments are each RcAnd RdIt independently is hydrogen, C1-3Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-6Cycloalkanes Base, C3-6Cycloalkenyl group, C2-6Heterocyclic radical, C6-10Aryl, C1-6Heteroaryl, C3-6Cycloalkyl C1-3Alkyl, C3-6Cycloalkenyl group C1-3Alkyl, C2-6Heterocyclic radical C1-3Alkyl, C6-10Aryl C1-3Alkyl or C1-6Heteroaryl C1-3Alkyl；Each RcAnd RdIndividually optionally by 1,2,3, 4th, 5 or 6 R2Substituted；
Wherein R2With implication as described in the present invention.
Some of embodiments are each R2Independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, oxo (=O), C1-4Alkyl, halo C1-4Alkyl, the C of hydroxyl substitution1-3Alkyl, the C of cyano group substitution1-3Alkyl, C2-4Alkene Base, C2-4Alkynyl, C1-3Alkoxy or C1-3Alkylamino.
Some of embodiments are each RA7、RA8、RA9、RA10And RA11Independently be hydrogen, deuterium, halogen, cyano group, hydroxyl, Nitro, amino, carboxyl, oxo (=O), methyl, ethyl, propyl group, isopropyl, ethyoxyl, propoxyl group, methoxymethoxy, first Epoxide ethyoxyl, methoxy propoxy, (ethoxymethyl) epoxide, ethoxy ethoxy, benzyl, pyridine -2- ylmethyls, pyridine -3- Ylmethyl, pyridin-4-yl methyl, phenoxy group, benzyloxy, thiazolylmethyloxy, methyl substituted thiazolylmethyloxy ,- (CH2)z- C (=O)-NH- cyclopropyl ,-(CH2)z- C (=O)-NH- cyclobutyl ,-(CH2)z- C (=O)-NH- cyclopenta ,- (CH2)z- C (=O)-NH- cyclohexyl ,-(CH2)z- C (=O)-NH- phenyl or trifluoromethyl substitution-(CH2)z- C (=O)- NH- phenyl；
Wherein z has implication as described in the present invention.
On the other hand, the present invention relates to a kind of compound, it is for the compound with one of following structure or with following One of the stereoisomers of structural compounds, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, generation Thank product, pharmaceutically acceptable salt or prodrug：
The application of compound and its pharmaceutically acceptable salt of the present invention also comprising the present invention, for producing medical product Treat autoimmune disease or proliferative diseases, including those are described in the invention.The compound of the present invention is equally used for giving birth to Produce a kind of pharmaceuticals to be used for mitigating, prevent, the disease that control or treatment are mediated by B cell.
Can be selected from tumor disease, proliferative diseases, allergic disease, autoimmunity by the disease of B cell mediation At least one of disease and diseases associated with inflammation.
The present invention includes pharmaceutical composition, and the pharmaceutical composition includes formula (I), formula (II), formula (IIa), formula (III), formula (IIIa), the compound representated by formula (IIIb), formula (IIIc) or formula (IV) and at least one pharmaceutically acceptable carrier, it is auxiliary Agent or effective treatment dosage with reference to needed for of diluent.
It is of the invention equally to include treatment autologous patient immunological diseases or proliferative diseases, or the method sensitive to this illness, This method includes and uses formula (I), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc) or formula (IV) The therapeutically effective amount of representative compound is treated to patient.
Unless otherwise indicated, all stereoisomer of compound, geometric isomer, the tautomerism of the present invention Body, raceme, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt and prodrug belong to this hair Bright scope.
The compound that the present invention describes can have one or more stereocenters, and each center may have R Or S configurations.Compound provided by the invention includes the form of all diastereoisomers, enantiomter and epimer, And its suitable mixture.If desired, stereoisomer can be obtained by methods known in the art, such as pass through chirality Chromatogram post separation stereoisomer.
The present invention compound salt, include be used for prepare or purify formula (I), formula (II), formula (IIa), formula (III), Formula (IIIa), formula (IIIb), the intermediate or formula (I) of formula (IIIc) or compound shown in formula (IV), formula (II), formula (IIa), formula (III), the salt of formula (IIIa), formula (IIIb), formula (IIIc) or the enantiomter of the separation of compound shown in formula (IV), but differ Surely it is pharmaceutically acceptable salt.
In addition, compound disclosed by the invention including their salt, with their hydrate forms or can also include it The form of solvent (such as ethanol, DMSO, etc.) obtains, for their crystallization.Compound disclosed by the invention can be with medicine Acceptable solvent (including water) inherently or by design forms solvate on；Therefore, it is contemplated that including solvent Change and unsolvated form.
Any structural formula that the present invention provides, which is also intended to, represents these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the formula that there is the compound of isotope enrichment the present invention to provide is described, except one or more Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Include the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H,3H,11C,13C,14C,15N,17O,18O,18F,31P,32P,35S,36Cl and125I。
On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its In radio isotope be present, such as3H,14C and18F those compounds, or non radioactive isotope wherein be present, such as2H and13C.The compound of such isotope enrichment can be used for metabolism research (to use14C), Reaction kinetics research are (using for example2H or3H), detection or imaging technique, such as positron emission tomography (PET) or including medicine or substrate tissue measure of spread Single photon emission computed tomography (SPECT), or available in the radiotherapy of patient.18The compound of F enrichments to PET or It is especially desirable for SPECT researchs.The formula (I) of isotope enrichment, formula (II), formula (IIa), formula (III), formula (IIIa), Formula (IIIb), formula (IIIc) or compound shown in formula (IV) can pass through routine techniques familiar to the person skilled in the art or this hair Described by embodiment and preparation process in bright original used unmarked examination is substituted using suitable isotope labeling reagent It is prepared by agent.
In addition, higher isotope particularly deuterium is (i.e.,2H or D) substitution some treatment advantages can be provided, these advantages are Brought by metabolic stability is higher.For example, Half-life in vivo increase or volume requirements reduce or therapeutic index obtains improving band Come.It should be appreciated that the deuterium in the present invention is counted as formula (I), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), the substituent of compound shown in formula (IIIc) or formula (IV).It is heavier such can be defined with isotope enrichment factor The concentration of isotope particularly deuterium.Term " isotope enrichment factor " used in the present invention refers to the same position of specified isotope Ratio between plain abundance and natural abundance.If the substituent of the compounds of this invention is designated as deuterium, the compound is to each finger There are at least 3500 (at each specified D-atoms 52.5% deuterium incorporation), at least 4000 (60% deuterium is mixed for fixed D-atom Enter), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporations), at least 5500 (82.5% deuterium incorporations), At least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporations), at least 6466.7 (97% deuterium incorporations), at least 6600 (99% deuterium incorporations) or the isotope enrichment factor of at least 6633.3 (99.5% deuterium incorporations).The present invention is pharmaceutically useful Solvate includes such as D that wherein recrystallisation solvent can be isotope substitution2O, acetone-d6、DMSO-d6Those solvations Thing.
The pharmaceutical composition and preparation of the compounds of this invention
One or more physiologically acceptable carriers compounding pharmaceutical composition in a conventional manner, the carrier can be used Including excipient and auxiliary material, it is advantageous to reactive compound being processed as can be with medicinal preparation.Appropriate preparation depends on choosing The method of administration selected.Technology, carrier and excipient known to any can be used suitably, and as understood in the art. The summary for the pharmaceutical composition that the present invention describes may refer to such as Remington:The Science and Practice of Pharmacy, the 19th edition (Easton, Pa.:Mack Publishing Company,1995)；Hoover,John E., Remington′s Pharmaceutical Sciences,Mack Publishing Co.,Easton,Pennsylvania, 1975；Liberman, H.A. and Lachman, L. write, Pharmaceutical Dosage Forms, Marcel Decker, NewYork,N.Y.,1980；And《Pharmaceutical Dosage Forms and Drug Delivery Systems》 7th edition (Lippincott Williams＆Wilkins, 1999), it is fully incorporated at this by quoting in the present invention.
The pharmaceutical composition that the present invention uses refers to one or more compounds of the invention with other chemical constituents for example Carrier, stabilizer, diluent, dispersant, suspending agent, the mixture of thickener and/or excipient.Described pharmaceutical composition is favourable Organism is given in compound.In treatment provided by the invention or application method is put into practice, it will be treated with pharmaceutical composition effective The compound that the present invention of amount describes gives the mammal with disease to be treated, obstacle or illness.Preferably, the food in one's mouth Newborn animal is people.Therapeutically effective amount can change very big, age of the order of severity, subject depending on disease and relatively strong The other factorses such as the effect of health situation, compound used.
Carrier is included in any excipient commonly used in pharmacy, and by based on the phase with compound disclosed by the invention Capacitive is selected.Exemplary carrier material include for example adhesive, suspending agent, disintegrant, filler, surfactant, Solubilizer, stabilizer, lubricant, wetting agent, diluent etc..
Suspending agent include such as polyvinylpyrrolidone such as polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, Polyvinylpyrrolidone K25 or PVP K30, vinyl pyrrolidone/vinyl acetate copolymer (S630), gather Ethylene glycol (such as the molecular weight of polyethylene glycol can be about 300 to about 6000 or about 3350 to about 4000 or about 7000 to about 5400), sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, acetic acid-stearic acid hydroxymethyl cellulose, poly- mountain For example gummy tragacanth of pear ester -80, hydroxyethyl cellulose, sodium alginate, gummy class and gummy Arabic gum, guar gum, Huang Virgin rubber class includes xanthans, sugar, cellulose family such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl Ylmethyl cellulose, hydroxyethyl cellulose, Tween-80, sodium alginate, polyethoxylated sorbitan monolaurate, poly- ethoxy The compounds such as base sorbitan monolaurate, PVP.
Disintegrant or distintegrant promote the decomposition or disintegration of material.
Filler includes such as lactose, calcium carbonate, calcium phosphate, calcium monohydrogen phosphate, calcium sulfate, microcrystalline cellulose, flour Element, glucose, dextrates, glucan, starch, pregelatinized starch, sucrose, xylitol, Lactitol, mannitol, mountain The compounds such as pears alcohol, sodium chloride, polyethylene glycol.
Surfactant includes such as lauryl sodium sulfate, docusate sodium, tween (Tween) 60 or the second of 80, glycerine three Acid esters, vitamin E TPGS, single oleic acid sorbitan esters, polyoxyethylene list oleic acid sorbitan esters, polysorbate, In terms of edible safety, vermicelli are subjected to desulfurization process, utilized.
Solubilizer includes such as triacetin, triethyl citrate, ethyl oleate, ethyl caprilate, lauryl sodium sulfate, more DOSS, vitamin E TPGS, dimethyl acetamide, 1-METHYLPYRROLIDONE, N- hydroxyethylpyrrolidines ketone, polyvinyl pyrrole Alkanone, hydroxypropyl methyl cellulose, hydroxypropyl cyclodextrin, ethanol, n-butanol, isopropanol, cholesterol, cholate, polyethylene glycol 200-600, Tetrahydrofurfuryl polyethylene glycol ether (glycofurol), ethylene glycol monomethyl ether (transcutol), propane diols and two The compounds such as methyl Coronex.
Stabilizer includes the compound such as any antioxidant, buffer, acid, preservative.
Dispersant and/or viscosity modifier include such material, and it passes through liquid medium or method of granulating or mixing side The diffusion of method control medicine and uniformity.In some embodiments, these assistant agents also promote coating or eroding matrix Effect.
Diluent is the compound for diluting target compound before medicine is passed.Diluent can be used for making compound Fig. 2 is Actor-Critic structure charts.(it can also provide control or maintain the salt being dissolved in cushioning liquid PH) it is used as the salting liquid of diluent, including but not limited to phosphate-buffered in the art.In some embodiments, it is dilute The volume of agent increase composition is released to promote to compress, or produces the volume for the homogeneity mixing for being sufficiently used for capsule filling.
In some embodiments, composition can also include one or more pH adjusting agents or buffer, including acid, alkali Or buffer.It is in order to which the pH of composition is maintained within the acceptable range including the desired amount of these acid, alkali and buffers.
In other embodiments, composition can also include one or more salt of required amount so that the weight of composition Measure Morie osmolarity within the acceptable range.
Terminology used in the present invention " pharmaceutical composition " refer to by least one active component mixing or combine Product, and the fixation including active component and non-fixed combinations.Term " fixed Combination " refers to active component, such as the present invention The compound of description and assistant agent (co-agent), both given patient simultaneously in the form of single entirety or dosage.Term " non-fixed combinations " refer to active component, such as the compound that describes of the present invention and mixture, its as separated individual simultaneously, one Rise or continuously give patient without specific interval time restriction, wherein this gives having in patient's body two kinds of compounds of offer Effect is horizontal.528322 Shunde District, Fushan City, Guangdong Province Le Liu streets Lian Du villages Tian Ren industry parks.
Pharmaceutical composition of the present invention can be with solid such as tablet or filling capsule, semisolid, powder, sustained release preparation or liquid As solution, supensoid agent, emulsion, elixir or filling capsule use；Or used for the suppository form of rectum or vaginal application；Or The form of the sterile injectable solution used for parenteral uses.
Typical preparation includes about 5% to about 95% a kind of reactive compound or various active compound (w/w).Properly Formulation include but is not limited to the agent such as aqueous oral dispersion, liquid preparation, gel, syrup, elixir, paste, supensoid agent Type, for the orally ingestible of patient to be treated, solid oral dosage form, aerosol, controlled release preparation, dissolution formulation, effervescent formulation, jelly Dry preparation, tablet, powder, pill, dragee, capsule, sustained release preparation, delayed release dosage system, pulsation delivery formulations, more granular preparations With releasing and controlled release preparation for mixing.
In Remington：Pharmaceutical science and put into practice (Remington:The Science and Practice of Pharmacy, 1995, edited by E.W.Martin, Mack publishing company, the 19th edition, Easton, Pennsylvania) described in Suitable preparation and pharmaceutical carrier, diluent and excipient.Experienced formulation science man can be in description of the invention Change preparation in the range of teaching to provide several formulations, it is used for the concrete ways applied, the composition without making the present invention It is unstable or damage their therapeutic activity.
The purposes of the compounds of this invention
The compounds of this invention can be effectively used for treatment and BTK relevant diseases, i.e., related to B cell and/or mast cell Disease, these diseases include, but are not limited to：
Allergic disease, such as allergy, allergic reaction, allergic conjunctivitis, allergic rhinitis or atopic dermatitis；
Autoimmune disease, for example, inflammatory bowel disease, arthritis, lupus, rheumatic arthritis, rheumatoid arthritis, Psoriasis arthropathica, osteoarthritis, Still disease, adolescent arthritis, diabetes, myasthenia gravis, bridge this thyroid gland Inflammation, Order thyroiditis, Graves disease, rheumatoid arthritis syndrome, multiple sclerosis, Guillain-Barre syndrome, Acute diseminated encephalomyelitis, Addision's disease, opsoclonus-myoclonic syndrome, ankylosing spondylitis, anti-phospholipid antibody are comprehensive Simulator sickness, alpastic anemia, oneself immunity hepatitis, chylous diarrhea, goodpasture's syndrome, idiopathic thrombocytopenic Purpura, optic neuritis, chorionitis, PBC, Reiter syndrome, takayasu's arteritis, temporal arteritis, warm type Autoimmune hemolytic anemia, Wegner's granulomatosis, psoriasis, alopecia universalis, behcet disease, confirmed fatigue, family Property dysautonomia, mullerianosis, interstitial cystitis, neuromyotonia, chorionitis or Vulvodynia；
Heteroimmune condition or disease, such as graft versus host disease(GVH disease), transplanting, blood transfusion, allergic reaction, allergy, I Type hypersensitivity, allergic conjunctivitis, allergic rhinitis or atopic dermatitis；
Inflammatory disease, such as asthma, appendicitis, blepharitis, capillary bronchitis, bronchitis, bursal synovitis, cervicitis, courage Guan Yan, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, Enteritis, enterocolitis, epicondylitis, epididymitis, fascitis, fibrositis, gastritis, gastroenteritis, hepatitis, suppurative hidradenitis, Laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, ephritis, oaritis, orchitis, osteitis, otitis, pancreatitis, the parotid gland Inflammation, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, rectitis, prostatitis, pyelonephritis, Rhinitis, salpingitis, nasosinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis or vulva It is scorching；
Cancer, in some embodiments, cancer is B cell proliferative disease, such as diffusivity large B cell lymphoid tumor, Follicular lymphoma, chronic lymphocytic leukemia, chronic lymphocytic leukemia, B cell pre-lymphocytic leukemia, leaching Bar plasmacytic lymphoma/macroglobulinemia Waldenstron, splenic marginal zone lymthoma, plasma cell myeloma, thick liquid cell Knurl, extranodal marginal zone B cell lymphoma, lymphoma nodal marginal zone B cell, mantle cell lymphoma, mediastinum (thymus gland) big B Cell lymphoma, intravascular large B cell lymphoma, lymphoma primary effusion, Burkitt lymphoma/leukaemia or lymthoma Sample granulomatosis；
Thrombotic disease, for example, miocardial infarction, angina pectoris, postangioplasty again occlusion, postangioplasty again Occlusion, ISR, apoplexy, transient office after aortocoronary bypass again after narrow, aortocoronary bypass Portion's ischemic, peripheral arterial occlusive disease, pulmonary embolism or dvt are formed；
And other suppress the disease that BTK kinase activities are benefited to patient, include but is not limited to, lobular carcinoma, cellule Lung cancer, non-small cell lung cancer, melanoma, brain tumor, carcinoma of urinary bladder, stomach cancer, oophoroma, cancer of pancreas, breast cancer, head and neck cancer, uterus Neck cancer, carcinoma of endometrium, the carcinoma of the rectum, kidney, cancer of the esophagus, prostate cancer, thyroid cancer, osteocarcinoma, cutaneum carcinoma, colon cancer, female Genital tract knurl, lymthoma, Huppert's disease and carcinoma of testis etc..
Conjoint therapy
The pharmaceutical composition that the present invention describes, it can also be used in combination with other well known therapeutic reagents, their treatment Value is selected for the illness to be treated.The example of other therapeutic reagents, include but is not limited to, chemotherapeutics or antiproliferative, resist Scorching medicine, immunomodulator or immunodepressant, neurotrophic factor, the activating agent for treating angiocardiopathy, for treating The activating agent of diabetes and the activating agent for treating autoimmune disease.
In some of these embodiments, other therapeutic reagents include but is not limited to, tyrosine kinase inhibitor (Ru Axi For Buddhist nun, Dasatinib, Conmana, Ibrutinib etc.), topoisomerase enzyme inhibitor (such as Hycamtin), protein kinase C Inhibitor (such as AEB-071), sphingosine-1-phosphate receptor activator (such as FTY720, KRP-203), anti-T cell are immunized Globulin (such as AtGam), the antibody (such as daclizumab) of anti-IL-2 acceptors, acid amides (CTX), ifosfamide (IFO), It is adriamycin (ADM), daunorubicin (DNR), vincristine (VCR), vinblastine (VBL), etoposide (VP16), brave and fierce (Vumon), carboplatin (CBP) and methotrexate (MTX) (MTX) cyclosporin A, tacrolimus, sirolimus, everolimus, sulphur azoles are fast Purine, cloth quinoline that, leflunomide, LEA-29Y, anti-cd 3 antibodies (such as 0KT3), aspirin, B7-CD28 blocker molecules (such as Belatacept, Abatacept etc.), CD40-CD154 blocker molecules (such as anti-CD 40 antibodies etc.), paracetamol, brufen, Naproxen, piroxicam and anti-inflammatory steroid class (such as prednisolone or dexamethasone).
General building-up process
Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, the wherein definition of substituent such as formula (I), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc) or shown in formula (IV).Following reaction scheme and embodiment are used to present disclosure be further illustrated.
Those skilled in the art will realize that：Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and other methods of the compound for preparing the present invention are considered as the model in the present invention Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention Completed by method of modifying, such as appropriate protection interference group, by using other known reagent except described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified during use, unless other aspects show.In general reagent is from the western Gansu Province chemical industry in Shantou Imperial chemistry examination is risen in factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Qingdao Agent Co., Ltd and Haiyang Chemical Plant, Qingdao are commercially available.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by metallic sodium backflow.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride backflow.Ethyl acetate, petroleum ether, n-hexane, DMA and N, N- Dimethylformamide is to dry to use in advance through anhydrous sodium sulfate.
Reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects below Show), reaction bulb all by syringe squeezed into beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.The survey of proton nmr spectra Strip part is：Under room temperature condition, Brooker (Bruker) 400MHz or 600MHz nuclear magnetic resonance spectrometer, with CDC13, d6- DMSO, CD3OD Or d6- acetone is solvent (reporting in units of ppm), and reference standard is used as by the use of TMS (0ppm) or chloroform (7.26ppm).When going out When existing multiplet, following abbreviation will be used：S (singlet, unimodal), d (doublet, bimodal), t (triplet, three Weight peak), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, double doublet), ddd (doublet of doublet of doublets, double two times of doublets), dt (doublet of triplets, double triplets).Coupling constant, represented with hertz (Hz).
The condition of Algorithm (MS) data determination is：Agilent 6120Quadrupole HPLC-MS (pillars Model：Zorbax SB-C18,2.1x 30mm, 3.5 μm, 6min, flow velocity 0.6mL/min, mobile phase：5%-95% (contains The CH of 0.1% formic acid3CN) (H of 0.1% formic acid is being contained2O the ratio in))), detected in 210/254nm with UV, with electron spray electricity From pattern (ESI).
The characteristic manner of compound purity is：The preparative high performance liquid chromatographies of Agilent 1260 (Pre-HPLC) or The preparative high performance liquid chromatographies of Calesep Pump 250 (Pre-HPLC) (pillar model：NOVASEP, 50/80mm, DAC), 210nm/254nm is detected with UV.
The use of brief word below is through the present invention：
HPLC high performance liquid chromatography；H2O water；CD3OD deuterated methanols；CH3CN, MeCN acetonitrile；CDCl3Deuterochloroform；DMAP DMAP；DMSO dimethyl sulfoxide (DMSO)s；DMF N,N-dimethylformamides；EtOAc ethyl acetate；PE petroleum ethers；Pd (dppf)Cl2[double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride；Carbon -7- the alkene of DBU 1,8- diazabicylos 11； DIAD diisopropyl azodiformates；DMF N,N-dimethylformamides；TEA triethanolamines；G grams；Mg milligrams；Mol moles； Mmol mMs；H hours；Min minutes；L liters；ML, ml milliliter；M mol/L.
Synthetic method one
Target compound 1 can be prepared by synthetic method one, and wherein X and Ay have to be contained as described in the present invention Justice.Compound 1-1 (synthetic method is referring to embodiment 1) and compound 1-2 reacts to obtain target compound 1.
Synthetic method two：
Target compound 2 can be prepared by synthetic method two, and wherein X and Cy1 have to be contained as described in the present invention Justice.Compound 1-1 (synthetic method is referring to embodiment 1) and compound 2-2 reacts to obtain target compound 2.
Synthetic method three：
Target compound 3 can be prepared by synthetic method three, and wherein Cy2 has implication as described in the present invention. Compound 1-1 (synthetic method is referring to embodiment 1) and compound 3-2 reacts to obtain target compound 3.
Embodiment
Embodiment 1
(R) -1- (3- (4- amino -3- (3- (3- (benzyloxy) phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4- D] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of iodo- 1H- pyrazolos [3,4-d] pyrimidine -4- amine of compound 3-
1H- pyrazolos [3,4-d] pyrimidine -4- amine (18.0g, 130.54mmol) is dissolved in DMF (150mL), then N- N-iodosuccinimides (45g, 195.81mmol, Aldrich) are slowly added into reaction solution, stirring reaction 12 is small at 80 DEG C When.Stop heating, cooling, water (200mL) is added into reaction solution, filter, wash (80mL), ethanol (60mL) is washed, and is dried, is obtained To gray solid 25.8g, yield：75.7%.LC-MS:(pos.ion)m/z:261.9[M+1]+.
Step 2：The synthesis of compound (S)-tert-butyl group 3- ((mesyl) epoxide) piperidines -1- carboxylates
(S)-tert-butyl group 3- hydroxy piperidine -1- carboxylates (20.0g, 97.1mmol) are dissolved in dichloromethane (200mL), Then triethylamine (18mL, 126mmol) is added into reaction solution, add under ice-water bath mesyl chloride (8.3mL, 107mmol) and DMAP (1.21g, 9.71mmol).It is stirred at room temperature 12 hours, dichloromethane (150mL) extraction, saturated aqueous common salt Wash (60mL), anhydrous sodium sulfate drying, remove solvent, silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v) under reduced pressure =6/1) white solid 21g, yield, are obtained：77.4%.
LC-MS(pos.ion)m/z:224.1(M-55).
Step 3：Compound (R)-tert-butyl group 3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidines - The synthesis of 1- carboxylates
Iodo- 1H- pyrazolos [3, the 4-d] pyrimidine -4- amine (5.0g, 18.77mmol) of 3- are dissolved in DMF (150mL), so (S)-tert-butyl group 3- ((mesyl) epoxide) piperidines -1- carboxylates (17.5g, 56.4mmol), carbon are added in backward reaction solution Sour caesium (18.5g, 56.2mmol) and DMAP (3.5g, 28mmol).Stir 8 hours at 90 DEG C, after having reacted, subtract DMF is evaporated off in pressure, dichloromethane (150mL) extraction, saturated common salt washing (100mL), anhydrous sodium sulfate drying, removes under reduced pressure molten Agent, silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains product 3.4g, yield：41%.
LC-MS(pos.ion)m/z:445.27[M+1]+.
Step 4：The synthesis of the iodo- 1- of compound (R) -3- (piperidines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -4- amine
By (R)-tert-butyl group 3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidines -1- carboxylates (1.0g, 2.25mmol) is dissolved in dioxane (6mL), and hydrochloric acid (4N, 6mL) is then added into reaction solution.It is stirred at room temperature 16 hours, after having reacted, dilute sodium hydrate aqueous solution is added, is adjusted to pH=9, dichloromethane (150mL) extraction, saturated common salt Wash (60mL), anhydrous sodium sulfate drying, remove solvent, silica gel column chromatography separating purification (DCM/MeOH (v/v)=12/ under reduced pressure 1-6/1), product 700mg, yield are obtained：90%.
LC-MS(pos.ion)m/z:345.15[M+1]+.
Step 5：Compound (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidines -1- Base) propyl- 2- alkene -1- ketone synthesis
The iodo- 1- of (R) -3- (piperidines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -4- amine (5g, 14.528mmol) is dissolved in In dichloromethane (250mL), sequentially added at 0 DEG C triethylamine (5.5mL, 36.32mmol) and three chlorpromazine chlorides (3mL, 29.056mmol), reaction 4 hours is stirred at room temperature, is slowly added to DBU (22mL, 145.28mmol), reacts at room temperature 12 hours.Instead After answering completely, saturated aqueous common salt (150mL) is washed three times.Organic phase anhydrous sodium sulfate drying, concentration, silica gel column chromatography separating purification (DCM/MeOH (v/v)=80/1-60/1), obtains faint yellow product 1.2g, yield：21%.
LC-MS:(pos.ion)m/z:399.04[M+1]+.
Step 6：The synthesis of compound 3- (benzyloxy) phenol
Resorcinol (3g, 26.7mmol) is dissolved in DMF (60mL), then add Anhydrous potassium carbonate (4.5g, 32.04mmol) and benzyl chloride (3.7mL, 32.04mmol, 1.1g/mL), heating reflux reaction 6h.Stop reaction, into reaction solution Add water (100mL), add watery hydrochloric acid regulation pH to 1, ethyl acetate extracts three times (150mL).Merge organic phase, anhydrous sodium sulfate Dry, concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=10/1), obtain pale yellow oily liquid 1.95g, produce Rate：36.5%.
LC-MS:(pos.ion)m/z:201.09[M+1]+.
Step 7：The synthesis of compound 1- (benzyloxy) -3- (propyl- 2- alkynes -1- bases epoxide) benzene
3- (benzyloxy) phenol (1g, 4.995mmol) is dissolved in acetone (35mL), addition Anhydrous potassium carbonate (2.1g, 14.99mmol) and 3- propargyl bromides (0.65mL, 7.493mmol).Replace nitrogen three times, under nitrogen protection, heating reflux reaction 24 Hour.After reaction completely, filtering, filtrate is concentrated, silica gel column chromatography separating purification (PE/EtOAc (v/v)=60/1), is obtained light Yellow oily liquid 0.92g, yield：77%.
LC-MS:(pos.ion)m/z:239.10[M+1]+.
Step 8：Compound (R) -1- (3- (4- amino -3- (3- (3- (benzyloxy) phenoxy group) propyl- 1- alkynes -1- bases) -1H- Pyrazolo [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (70mg, 0.175mmol) is dissolved in DMF (10mL), continuously adds 1- (benzyloxy) -3- (propyl- 2- alkynes -1- bases epoxide) benzene (65mg, 0.263mmol), cuprous iodide (7mg, 0.035mmol), triethylamine (11mg, 0.105mmol) and four (triphenylphosphines) Palladium (10mg, 0.0087mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filtering, concentrated solvent, adds Saturated aqueous common salt (100mL), dichloromethane (150mL) extraction.Silica gel thin-layer analysis isolates and purifies (PE/EtOAc (v/v)=1/5), Obtain white solid 42mg, yield：46.9%.
LC-MS:(pos.ion)m/z:509.23[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.24 (s, 1H), 7.45 (d, J=7.3Hz, 2H), 7.37 (t, J= 7.2Hz, 1H), 7.34-7.28 (m, 1H), 7.24 (t, J=8.1Hz, 1H), 6.93-6.79 (m, 1H), 6.75 (s, 1H), 6.68 (dd,J1=17.0Hz, J2=7.6Hz, 2H), 6.19-6.01 (m, 1H), 5.78-5.53 (m, 1H), 5.14 (s, 2H), 5.11 (s,2H),4.72–4.56(m,1H),4.56–4.44(m,0.5H),4.31–4.12(m,1H),4.10–3.98(m,0.5H), 3.65–3.53(m,0.5H),3.20–3.04(m,1H),2.94–2.82(m,0.5H),2.25–2.12(m,1H),2.12–2.02 (m,1H),1.92–1.79(m,1H),1.62–1.49(m,1H).
Embodiment 2
(R) -1- (3- (4- amino -3- (3- (3- ((2- methylthiazol -5- bases) methoxyl group) phenoxy group) propyl- 1- alkynes -1- Base) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound (2- methylthiazol -5- bases) methanol
5- aldehyde radical -2- methylthiazols (1.65g, 12.3mmol) are dissolved in methanol (50mL), 0 DEG C of addition sodium hydride (0.8g, 21.02mmol), continue to react 15min, react 3h at room temperature.After reaction completely, ammonium chloride saturated solution is added (100mL), ethyl acetate (200mL) extraction, merge organic phase, anhydrous sodium sulfate drying, filter, concentration, obtain yellow oily Liquid 1.45g, yield：91.7%.
LC-MS:(pos.ion)m/z:130.03[M+1]+.
Step 2：The synthesis of compound 3- ((2- methylthiazol -5- bases) methoxyl group) phenol
(2- methylthiazol -5- bases) methanol (938mg, 7.26mmol) and resorcinol (800mg, 7.26mmol) are dissolved In THF (50mL), triphenylphosphine (2.9g, 10.89mmol) and DIAD (2.17mL, 10.89mmol), nitrogen are then sequentially added Under gas shielded, reaction 12h is stirred at room temperature.After reaction completely, saturated aqueous common salt (100mL), dichloromethane (150mL) extraction are added Take, merge organic phase, anhydrous sodium sulfate drying, concentrated solvent.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/ 1) light yellow viscous liquid 1.5g (impure, to be not easy to separate), yield, are obtained：93%.
LC-MS(pos.ion)m/z:222.05[M+1]+.
Step 3：The synthesis of compound 2- methyl -5- ((3- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) methyl) thiazole
3- ((2- methylthiazol -5- bases) methoxyl group) phenol (1.6g, 7.2mmol) is dissolved in acetone (50mL), added Anhydrous potassium carbonate (3g, 22mmol) and 3- propargyl bromides (1.2mL, 14mmol).Replace nitrogen three times, under nitrogen protection, heat back Stream reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v)=10/ are concentrated 1) pale yellow oily liquid 450mg, yield, are obtained：24%.LC-MS:(pos.ion)m/z:260.07[M+1]+.
Step 4：Compound (R) -1- (3- (4- amino -3- (3- (3- ((2- methylthiazol -5- bases) methoxyl group) phenoxy group) Propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (130mg, 0.326mmol) is dissolved in DMF (15mL), continuously adds 2- methyl -5- ((3- (propyl- 2- alkynes -1- bases epoxide) benzene Epoxide) methyl) thiazole (169mg, 0.652mmol), cuprous iodide (13mg, 0.065mmol), triethylamine (0.03mL, 0.195mmol) and tetrakis triphenylphosphine palladium (19mg, 0.016mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, are stopped Reaction, filtering, concentrated solvent, add saturated aqueous common salt (100mL), dichloromethane (150mL) extraction.Silica gel thin-layer analysis separation is pure Change (DCM/MeOH (v/v)=30/1), obtain oily yellow solid 40mg, yield：23.1%.
LC-MS:(pos.ion)m/z:530.19[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.24 (s, 1H), 7.70 (s, 1H), 7.24 (t, J=8.1Hz, 1H), 6.95-6.80 (m, 1H), 6.76 (s, 1H), 6.71 (d, J=8.1Hz, 1H), 6.66 (d, J=7.9Hz, 1H), 6.16- 6.03(m,1H),5.73–5.56(m,1H),5.30(s,2H),5.15(s,2H),4.62(s,1H),4.54–4.44(m, 0.5H),4.31–4.14(m,1H),4.09–4.00(m,0.5H),3.64–3.51(m,0.5H),3.20–3.04(m,1H), 2.92–2.83(m,0.5H),2.61(s,3H),2.21–2.11(m,1H),2.09–2.00(m,1H),1.92–1.78(m,1H), 1.60–1.47(m,1H).
Embodiment 3
(R) -1- (3- (4- amino -3- (3- (3- fluorophenoxies) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine - 1- yls) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of the fluoro- 3- of compound 1- (propyl- 2- alkynes -1- bases epoxide) benzene
M fluorophenol (1g, 8.92mmol) is dissolved in acetone (35mL), addition Anhydrous potassium carbonate (3.7g, 27.762mmol) and 3- propargyl bromides (1.15mL, 13.381mmol).Replace nitrogen three times, under nitrogen protection, heating reflux reaction 24 hours.After reaction completely, filtering, filtrate is concentrated, silica gel column chromatography separating purification (PE/EtOAc (v/v)=90/1), is obtained Pale yellow oily liquid 1g, yield：74.6%.
1H NMR(400MHz,DMSO-d6):δ(ppm)7.34(dd,J1=15.4Hz, J2=8.0Hz, 1H), 6.90- 6.78 (m, 3H), 4.83 (d, J=2.4Hz, 2H), 3.59 (t, J=2.4Hz, 1H)
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (3- fluorophenoxies) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (85mg, 0.2135mmol) is dissolved in DMF (12mL), continuously add the fluoro- 3- of 1- (propyl- 2- alkynes -1- bases epoxide) benzene (48mg, 0.3202mmol), cuprous iodide (9mg, 0.0426mmol), triethylamine (13mg, 0.1281mmol) and tetrakis triphenylphosphine palladium (13mg,0.0106mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filtering, concentrated solvent, adds full With saline solution (100mL), dichloromethane (50mL × 3) extraction.Silica gel thin-layer analysis isolates and purifies (PE/EtOAc (v/v)=1/5), Obtain brown solid 27mg, yield：30.09%.
LC-MS:(pos.ion)m/z:421.17[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.24 (s, 1H), 7.37 (d, J=7.3Hz, 1H), 7.01 (d, J= 11.1Hz, 1H), 6.95 (d, J=7.3Hz, 1H), 6.90-6.77 (m, 1H), 6.77-6.55 (m, 1H), 6.18-6.00 (m, 1H),5.73–5.54(m,1H),5.19(s,2H),4.71–4.57(m,1H),4.53–4.42(m,0.5H),4.32–4.11(m, 1H),4.08–3.98(m,0.5H),3.67–3.54(m,0.5H),3.18–3.04(m,1H),2.95–2.85(m,0.5H), 2.22–2.12(m,1H),2.10–2.02(m,1H),1.94–1.84(m,1H),1.63–1.51(m,1H).
Embodiment 4
(R) -1- (3- (4- amino -3- (3- (3,5- difluoros phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] Pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of bis- fluoro- 5- of compound 1,3- (propyl- 2- alkynes -1- bases epoxide) benzene
3,5- difluorophenols (1.5g, 12mmol) are dissolved in acetone (50mL), addition Anhydrous potassium carbonate (4.8g, 35mmol) and 3- propargyl bromides (1.3mL, 15mmol).Replace nitrogen three times, under nitrogen protection, heating reflux reaction 24 hours.Instead After answering completely, filtering, filtrate is concentrated, silica gel column chromatography separating purification (PE), obtains pale yellow oily liquid 1.2g, yield： 62%.
1H NMR(400MHz,DMSO-d6):δ (ppm) 6.89-6.66 (3H, m), 4.86 (2H, d, J=2.3Hz), 3.62 (1H, t, J=2.3Hz)
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (3,5- difluoros phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (85mg, 0.2135mmol) is dissolved in DMF (12mL), continuously adds 1,3-, bis- fluoro- 5- (propyl- 2- alkynes -1- bases epoxide) benzene (75mg, 0.4269mmol), cuprous iodide (9mg, 0.0426mmol), triethylamine (13mg, 0.1281mmol) and four (triphenyls Phosphine) palladium (13mg, 0.0106mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filtering, concentrated solvent, adds Enter saturated aqueous common salt (100mL), dichloromethane (60mL × 3) extraction.Silica gel thin-layer analysis isolate and purify (DCM/MeOH (v/v)= 25/1) sepia solid 30mg, yield, are obtained：32.6%.
LC-MS:(pos.ion)m/z:439.16[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.25(s,1H),6.92(dd,J1=9.2Hz, J2=2.1Hz, 1H),6.89–6.80(m,2H),6.73–6.64(m,1H),6.14–6.04(m,1H),5.72–5.56(m,1H),5.21(s, 2H),4.68–4.59(m,1H),4.52–4.47(m,0.5H),4.23–4.14(m,1H),4.07–4.02(m,0.5H),3.62– 3.57(m,0.5H),3.16–3.08(m,1H),2.94–2.88(m,0.5H),2.19–2.15(m,1H),2.12–2.04(m, 1H),1.92–1.83(m,1H),1.59–1.51(m,1H).
Embodiment 5
(R) -1- (3- (4- amino -3- (3- (3- (benzyloxy) -5- fluorophenoxies) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 5- fluorobenzene -1,3- diphenol
Fluoro- 3, the 5- dimethoxy benzenes (2g, 12.808mmol) of 1- are dissolved in dichloromethane (50mL), nitrogen protection ,- Boron tribromide (26mL, 25.616mmol, 1M) is slowly dropped in above-mentioned solution at 35 DEG C, continues to react 30min, at room temperature Stirring reaction 3h.After reaction completely, methanol (20mL) and ice (20g) are added at 0 DEG C.Ethyl acetate (50mL × 3) extracts, and closes And organic phase, anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=30/1), is obtained To white solid 1.38g, yield：84.1%.
LC-MS:(pos.ion)m/z:129.03[M+1]+.
Step 2：The synthesis of compound 3- (benzyloxy) -5- fluorophenols
5- fluorobenzene -1,3- diphenol (1.38g, 10.8mmol) is dissolved in DMF (35mL), then adds Anhydrous potassium carbonate (2.26g, 16.2mmol) and benzyl chloride (1.3mL, 10.8mmol, 1.1g/mL), heating reflux reaction 10h.Stop reaction, to anti- Answer in liquid plus water (100mL), addition watery hydrochloric acid regulation pH to 1, ethyl acetate extract (50mL × 3).Merge organic phase, anhydrous sulphur Sour sodium is dried, and concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=10/1), obtains pale yellow oily liquid 480mg, yield：20%.
LC-MS:(pos.ion)m/z:219.08[M+1]+.
Step 3：The synthesis of the fluoro- 5- of compound 1- (benzyloxy) -3- (propyl- 2- alkynes -1- bases epoxide) benzene
3- (benzyloxy) -5- fluorophenols (450mg, 2.062mmol) are dissolved in acetone (20mL), add Anhydrous potassium carbonate (0.86g, 6.187mmol) and 3- propargyl bromides (0.36mL, 4.125mmol).Replace nitrogen three times, under nitrogen protection, heat back Stream reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v)=60/ are concentrated 1) pale yellow oily liquid 0.18g, yield, are obtained：34%.
LC-MS:(pos.ion)m/z:257.09[M+1]+.
Step 4：Compound (R) -1- (3- (4- amino -3- (3- (3- (benzyloxy) -5- fluorophenoxies) propyl- 1- alkynes -1- Base) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (110mg, 0.2762mmol) is dissolved in DMF (15mL), continuously adds the fluoro- 5- of 1- (benzyloxy) -3- (propyl- 2- alkynes -1- base oxygen Base) benzene (106mg, 0.4144mmol), cuprous iodide (11mg, 0.0552mmol), triethylamine (17mg, 0.1657mmol) and four (triphenylphosphine) palladium (16mg, 0.0138mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentration Solvent, add saturated aqueous common salt (100mL), dichloromethane (150mL) extraction.Silica gel thin-layer analysis isolates and purifies (PE/EtOAc (v/ V)=1/5), brown solid 51mg, yield are obtained：35%.
LC-MS:(pos.ion)m/z:527.21[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.24 (s, 1H), 7.44 (d, J=7.3Hz, 2H), 7.38 (t, J= 7.4Hz, 2H), 7.32 (t, J=7.3Hz, 1H), 6.89-6.78 (m, 1H), 6.73-6.64 (m, 1H), 6.64-6.59 (m, 2H),6.58–6.54(m,1H),6.15–6.03(m,1H),5.72–5.56(m,1H),5.16(s,2H),5.12(s,2H), 4.69–4.58(m,1H),4.54–4.47(m,0.5H),4.21–4.12(m,1H),4.08–4.02(m,0.5H),3.64–3.56 (m,0.5H),3.17–3.07(m,1H),2.93–2.85(m,0.5H),2.21–2.12(m,1H),2.10–2.03(m,1H), 1.92–1.84(m,1H),1.60–1.51(m,1H).
Embodiment 6
(R) -1- (3- (4- amino -3- (3- (3- ((3- luorobenzyls) epoxide) phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrazoles And [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 3- ((3- luorobenzyls) epoxide) phenol
Resorcinol (1.75g, 15.87mmol) is dissolved in DMF (40mL), then add Anhydrous potassium carbonate (2.2g, 15.87mmol) and a fluorine bromobenzyl (1g, 5.29mmol), 12h is reacted at room temperature.Stop reaction, water (100mL) added into reaction solution, Add watery hydrochloric acid regulation pH to 6, ethyl acetate extraction (50mL × 3).Merge organic phase, anhydrous sodium sulfate drying, concentration, silica gel Column chromatographic isolation and purification (PE/EtOAc (v/v)=15/1), obtains pale yellow oily liquid 800mg, yield：70%.
LC-MS:(pos.ion)m/z:219.08[M+1]+.
Step 2：The synthesis of the fluoro- 3- of compound 1- ((3- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) methyl) benzene
3- ((3- luorobenzyls) epoxide) phenol (800mg, 3.66mmol) is dissolved in acetone (30mL), adds Carbon Dioxide Potassium (1.53g, 11.00mmol) and 3- propargyl bromides (0.95mL, 11.00mmol).Replace nitrogen three times, under nitrogen protection, heating Back flow reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v)=40/ are concentrated 1) pale yellow oily liquid 450mg, yield, are obtained：69%.
LC-MS:(pos.ion)m/z:257.09[M+1]+.
Step 3：Compound (R) -1- (3- (4- amino -3- (3- (3- ((3- luorobenzyls) epoxide) phenoxy group) propyl- 1- alkynes - 1- yls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.301mmol) is dissolved in DMF (15mL), continuously adds the fluoro- 3- of 1- ((3- (propyl- 2- alkynes -1- bases epoxide) benzene oxygen Base) methyl) benzene (154mg, 0.602mmol), cuprous iodide (11mg, 0.0552mmol), triethylamine (17mg, 0.1657mmol) With tetrakis triphenylphosphine palladium (16mg, 0.0138mmol).Under nitrogen protections, 80 DEG C of reaction 15h are heated to, stops reaction, filters, Concentrated solvent, add saturated aqueous common salt (100mL), dichloromethane (150mL) extraction.Silica gel thin-layer analysis isolates and purifies (EtOAc/ MeOH (v/v)=40/1), obtain oily yellow solid 72mg, yield：45.3%.
LC-MS:(pos.ion)m/z:527.22[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.24(s,1H),7.42(dd,J1=14.1Hz, J2=7.5Hz, 1H), 7.32-7.22 (m, 3H), 7.14 (t, J=7.7Hz, 1H), 6.89-6.79 (m, 1H), 6.76 (s, 1H), 6.74-6.60 (m,3H),6.16–6.02(m,1H),5.73–5.55(m,1H),5.15(s,2H),5.14(s,2H),4.70–4.57(m,1H), 4.56–4.45(m,0.5H),4.30–4.12(m,1H),4.10–4.01(m,0.5H),3.64–3.53(m,0.5H),3.19– 3.03(m,1H),2.95–2.84(m,0.5H),2.23–2.12(m,1H),2.11–2.02(m,1H),1.96–1.80(m,1H), 1.62–1.48(m,1H).
Embodiment 7
(R) -1- (3- (4- amino -3- (3- (3- (pyridine -2- ylmethoxies) phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 3- (pyridine -2- ylmethoxies) phenol
Resorcinol (650mg, 5.78mmol) is dissolved in DMF (30mL), then add Anhydrous potassium carbonate (3.3g, 23.1mmol) with 2- (bromomethyl) pyridine hydrobromide salt (1.6g, 6.36mmol), 12h is reacted at room temperature.Stop reaction, to reaction In liquid plus water (100mL), addition watery hydrochloric acid regulation pH to 6, ethyl acetate extract (50mL × 3).Merge organic phase, anhydrous slufuric acid Sodium is dried, and concentration, silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains colourless liquid 1g, yield：85%.
LC-MS:(pos.ion)m/z:202.08[M+1]+.
Step 2：The synthesis of compound 2- ((3- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) methyl) pyridine
3- (pyridine -2- ylmethoxies) phenol (1g, 4.96mmol) is dissolved in acetone (45mL), adds Anhydrous potassium carbonate (2.77g, 19.87mmol) and 3- propargyl bromides (2.14mL, 24.848mmol).Replace nitrogen three times, under nitrogen protection, heat back Stream reaction 24 hours.After reaction completely, filtering, concentration filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v)=8/1), Obtain dark brown liquid 280mg, yield：23.54%.LC-MS:(pos.ion)m/z:240.10[M+1]+.
Step 3：Compound (R) -1- (3- (4- amino -3- (3- (3- (pyridine -2- ylmethoxies) phenoxy group) propyl- 1- alkynes - 1- yls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (100mg, 0.251mmol) is dissolved in DMF (15mL), continuously adds 2- ((3- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) first Base) pyridine (120mg, 0.502mmol), cuprous iodide (10mg, 0.0502mmol), triethylamine (18mg, 0.1657mmol) and Tetrakis triphenylphosphine palladium (15mg, 0.0125mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stop reaction, filtering is dense Contracting solvent, add saturated aqueous common salt (150mL), dichloromethane (70mL × 3) extraction.Silica gel thin-layer analysis isolates and purifies (DCM/ MeOH (v/v)=25/1), obtain brown solid 32mg, yield：25%.
LC-MS:(pos.ion)m/z:510.22[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.58 (d, J=4.3Hz, 1H), 8.24 (s, 1H), 7.82 (t, J= 7.0Hz, 1H), 7.52 (d, J=7.8Hz, 1H), 7.36-7.31 (m, 1H), 7.25 (t, J=8.2Hz, 1H), 6.88-6.80 (m, 1H), 6.77 (t, J=2.3Hz, 1H), 6.71 (dd, J1=8.3Hz, J2=2.0Hz, 1H), 6.67 (dd, J1=8.2Hz, J2=2.1Hz, 1H), 6.15-6.03 (m, 1H), 5.72-5.58 (m, 1H), 5.18 (s, 2H), 5.15 (s, 2H), 4.69-4.57 (m,1H),4.54–4.46(m,0.5H),4.29–4.12(m,1H),4.09–4.00(m,0.5H),3.64–3.54(m,0.5H), 3.16–3.05(m,1H),2.93–2.84(m,0.5H),2.21–2.12(m,1H),2.10–2.02(m,1H),1.92–1.82 (m,1H),1.59–1.50(m,1H).
Embodiment 8
(R) -1- (3- (4- amino -3- (3- (3- (benzyloxy) phenoxy group) -3- methyl butyl- 1- alkynes -1- bases) -1H- pyrazoles And [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 1- (benzyloxy) -3- ((2- methyl butyl- 3- alkynes -2- bases) epoxide) benzene
3- (benzyloxy) phenol (1g, 4.995mmol) is dissolved in acetone (40mL), addition Anhydrous potassium carbonate (2.1g, 14.99mmol) with KI (1g, 5.994mmol), the chloro- 3- methyl isophthalic acids of 3--butine (1.2mL, 9.99mmol) is slowly added dropwise Into above-mentioned solution, heating reflux reaction 48 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification are concentrated (PE/EtOAc (v/v)=100/1), obtains weak yellow liquid 320mg, yield：24%.
LC-MS:(pos.ion)m/z:267.13[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (3- (benzyloxy) phenoxy group) -3- methyl butyl- 1- alkynes -1- Base) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (160mg, 0.4018mmol) is dissolved in DMF (15mL), continuously adds 1- (benzyloxy) -3- ((2- methyl butyl- 3- alkynes -2- Base) epoxide) benzene (214mg, 0.8036mmol), cuprous iodide (16mg, 0.0803mmol), triethylamine (24mg, 0.2411mmol) and tetrakis triphenylphosphine palladium (24mg, 0.0200mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, are stopped Only react, filter, concentrated solvent, add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel thin-layer analysis point From purifying (DCM/MeOH (v/v)=20/1), oily yellow solid 44mg, yield are obtained：20%.
LC-MS:(pos.ion)m/z:537.26[M+1]+；
1H NMR(600MHz,CDCl3):δ (ppm) 8.28 (s, 1H), 7.35 (d, J=19.6Hz, 4H), 7.30-7.27 (m, 1H), 7.23-7.16 (m, 1H), 6.93-6.80 (m, 2H), 6.77-6.67 (m, 1H), 6.55 (d, J=42.4Hz, 1H), 6.37–6.20(m,1H),5.72–5.60(m,1H),5.02(s,2H),4.85–4.74(m,1H),4.68–4.59(m,0.5H), 4.27–4.06(m,1H),4.05–3.94(m,0.5H),3.67–3.55(m,0.5H),3.37–3.13(m,1H),3.13–3.02 (m,0.5H),2.34–2.25(m,1H),2.20–2.12(m,1H),1.96–1.89(m,1H),1.80(s,6H),1.71–1.64 (m,1H).
Embodiment 9
1- ((3R) -3- (4- amino -3- (3- hydroxyl -3- phenyl butyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine - 1- yls) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 2- phenyl -4- (trimethyl silicon substrate) butyl- 3- alkynes -2- alcohol
Front three ethyl-acetylene silicon (2.1mL, 15mmol, 0.695g/mL) is dissolved in THF (20mL), at -70 DEG C slowly Add n-BuLi (6.3mL, 15mmol, 0.153g/mL), stirring reaction 1h at -70 DEG C, by acetophenone (1.2mL, 10mmol, 0.695g/mL) it is added in above-mentioned reaction solution, continues to react 1h, be warmed to room temperature stirring reaction 30min, stop reaction.Add full With ammonium chloride solution (150mL), ethyl acetate extraction (60mL × 3).Merge organic phase, anhydrous sodium sulfate drying, concentration, silica gel Column chromatographic isolation and purification (PE/EtOAc (v/v)=80/1), obtains weak yellow liquid 1.6g, yield：71%.
LC-MS:(pos.ion)m/z:219.12[M+1]+.
Step 2：The synthesis of compound 2- phenyl butyl- 3- alkynes -2- alcohol
2- phenyl -4- (trimethyl silicon substrate) butyl- 3- alkynes -2- alcohol (630mg, 2.88mmol) is dissolved in methanol (15mL), Anhydrous potassium carbonate (1.4g, 10.10mmol) is added, at room temperature stirring reaction 3h.Stop reaction, filtering, collect filtrate, concentrate, Silica gel column chromatography separating purification (PE/EtOAc (v/v)=80/1), obtains weak yellow liquid 300mg, yield：71.4%.
LC-MS:(pos.ion)m/z:147.08[M+1]+.
Step 3：Compound 1- ((3R) -3- (4- amino -3- (3- hydroxyl -3- phenyl butyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (130mg, 0.3265mmol) is dissolved in DMF (15mL), continuously add 2- phenyl butyl- 3- alkynes -2- alcohol (100mg, 0.6529mmol), cuprous iodide (13mg, 0.0652mmol), triethylamine (20mg, 0.1959mmol) and tetrakis triphenylphosphine palladium (19mg,0.0163mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filtering, concentrated solvent, adds full With saline solution (100mL), dichloromethane (50mL × 3) extraction.Silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=20/ 1) oily yellow solid 55mg, yield, are obtained：40%.
LC-MS:(pos.ion)m/z:417.20[M+1]+；
1H NMR(600MHz,CDCl3):δ (ppm) 8.10 (d, J=24.3Hz, 1H), 7.79-7.63 (m, 2H), 7.46- 7.34(m,2H),7.33–7.28(m,1H),6.60–6.46(m,1H),6.33–6.21(m,1H),5.74–5.61(m,1H), 4.80–4.71(m,1H),4.59–4.48(m,0.5H),4.43–4.01(m,1H),3.97–3.88(m,0.5H),3.73–3.58 (m,0.5H),3.23–3.00(m,1H),2.86–2.76(m,0.5H),2.29–2.18(m,1H),2.18–2.10(m,1H), 1.97–1.91(m,1H),1.91–1.80(m,3H),1.71–1.52(m,1H).
Embodiment 10
(R) ((4- amino -3- (3- methyl -3- phenoxy group butyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] are phonetic by 3- by -1- Pyridine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound ((2- methyl butyl- 3- alkynes -2- bases) epoxide) benzene
Phenol (1.5g, 16mmol) is dissolved in acetone (50mL), adds Anhydrous potassium carbonate (6.6g, 48mmol) and iodate Potassium (3.2g, 19mmol), the chloro- 3- methyl isophthalic acids of 3--butine (3mL, 24mmol, 0.913g/mL) is slowly dropped to above-mentioned solution In, heating reflux reaction 48 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/ are concentrated V)=100/1), weak yellow liquid 400mg, yield are obtained：16%.
LC-MS:(pos.ion)m/z:161.09[M+1]+；
1H NMR(400MHz,DMSO-d6):δ (ppm) 7.31 (2H, t, J=7.9Hz), 7.16 (2H, d, J=7.9Hz), 7.05 (1H, t, J=7.3Hz), 3.63 (1H, s), 1.58 (6H, s)
Step 2：Compound (R) -1- (3- (4- amino -3- (3- methyl -3- phenoxy group butyl- 1- alkynes -1- bases) -1H- pyrazoles And [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (160mg, 0.4018mmol) is dissolved in DMF (15mL), continuously adds ((2- methyl butyl- 3- alkynes -2- bases) epoxide) benzene (130mg, 0.8036mmol), cuprous iodide (16mg, 0.0803mmol), triethylamine (24mg, 0.2411mmol) and four (triphens Base phosphine) palladium (24mg, 0.0200mmol).Under nitrogen protections, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentrated solvent, Add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v) =25/1) oily yellow solid 32mg, yield, are obtained：18.5%.
LC-MS:(pos.ion)m/z:431.22[M+1]+；
1H NMR(600MHz,CDCl3):δ (ppm) 8.28 (s, 1H), 7.31 (t, J=7.4Hz, 2H), 7.23 (d, J= 7.6Hz, 2H), 7.09 (t, J=7.0Hz, 1H), 6.67-6.48 (m, 1H), 6.36-6.23 (m, 1H), 5.70-5.55 (m, 1H),4.94–4.74(m,0.5H),4.68–4.54(m,1H),4.15–4.01(m,0.5H),3.75–3.59(m,0.5H), 3.30–3.05(m,1H),2.85–2.74(m,0.5H),2.37–2.24(m,1H),2.24–2.13(m,1H),1.99–1.94 (m,1H),1.82(s,6H),1.73–1.67(m,1H).
Embodiment 11
(R) -1-3- (4- amino -3- (3- (3- (benzyloxy) phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] Pyrimidine -1- bases) piperidines -1- formonitrile HCNs
Step 1：Compound (R) -3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidines -1- formonitrile HCNs Synthesis
The iodo- 1- of (R) -3- (piperidines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -4- amine (3g, 8.716mmol) is dissolved in In DMF (80mL), cesium carbonate (11.6g, 34.868mmol) is added.Be slowly added at 0 DEG C cyanogen bromide (1.9g, 17.434mmol), continue stirring reaction 30min, reaction 3 hours is stirred at room temperature.Stop reaction, filtering, concentrate filtrate, add full With saline solution (150mL), ethyl acetate extraction (100mL × 3), anhydrous sodium sulfate drying, concentration, silica gel column chromatography separating purification (DCM/MeOH (v/v)=60/1), obtains faint yellow solid 770mg, yield：24%.
LC-MS:(pos.ion)m/z:370.02[M+1]+.
Step 2：Compound (R) -3- (4- amino -3- (3- (3- (benzyloxy) phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidines -1- formonitrile HCNs synthesis
By (R) -3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidines -1- formonitrile HCNs (130mg, 0.352mmol) be dissolved in DMF (15mL), continuously add 1- (benzyloxy) -3- (propyl- 2- alkynes -1- bases epoxide) benzene (170mg, 0.704mmol), cuprous iodide (14mg, 0.0704mmol), triethylamine (14mg, 0.211mmol) and tetrakis triphenylphosphine palladium (21mg,0.0176mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filtering, concentrated solvent, adds full With saline solution (100mL), dichloromethane (50mL × 3) extraction.Silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=24/ 1) oily yellow solid 78mg, yield, are obtained：46.1%.
LC-MS:(pos.ion)m/z:480.21[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.26 (s, 1H), 7.45 (d, J=7.3Hz, 2H), 7.37 (t, J= 7.4Hz, 2H), 7.31 (t, J=7.1Hz, 1H), 7.24 (t, J=8.2Hz, 1H), 6.75 (s, 1H), 6.68 (dd, J1= 17.7Hz,J2=8.1Hz, 2H), 5.14 (s, 2H), 5.10 (s, 2H), 4.85-4.75 (m, 1H), 3.63-3.54 (m, 1H), 3.47–3.40(m,1H),3.40–3.37(m,1H),3.15–3.07(m,1H),2.14–2.04(m,1H),2.04–1.95(m, 1H),1.90–1.82(m,1H),1.81–1.71(m,1H).
Embodiment 12
(R) -3- (4- amino -3- (3- phenoxy group propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperazine Pyridine -1- formonitrile HCNs
Step 1：The synthesis of compound (propyl- 2- alkynes -1- bases epoxide) benzene
Phenol (1.5g, 16mmol) is dissolved in acetone (50mL), adds Anhydrous potassium carbonate (6.7g, 48mmol) and 3- bromines Propine (2.1mL, 24mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, heating reflux reaction 24 hours.React Quan Hou, filtering, filtrate is concentrated, silica gel column chromatography separating purification (PE/EtOAc (v/v)=70/1), obtains weak yellow liquid 1.2g, yield：57%.
LC-MS:(pos.ion)m/z:132.06[M+1]+.
Step 2：(4- amino -3- (3- phenoxy group propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] are phonetic by compound (R) -3- Pyridine -1- bases) piperidines -1- formonitrile HCNs synthesis
By (R) -3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidines -1- formonitrile HCNs (150mg, DMF (15mL) 0.406mmol) is dissolved in, continuously adds (propyl- 2- alkynes -1- bases epoxide) benzene (110mg, 0.812mmol), iodate is sub- Copper (16mg, 0.0812mmol), triethylamine (30mg, 0.243mmol) and tetrakis triphenylphosphine palladium (24mg, 0.0203mmol). Under nitrogen is protected, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentrated solvent, addition saturated aqueous common salt (100mL), two Chloromethanes (50mL × 3) extracts.Silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=22/1), obtains oily yellow solid 60mg, yield：39.5%.
LC-MS:(pos.ion)m/z:374.17[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.31 (s, 1H), 7.34 (t, J=7.6Hz, 2H), 7.09 (d, J= 7.9Hz, 2H), 7.00 (t, J=7.1Hz, 1H), 5.16 (s, 2H), 4.85-4.74 (m, 1H), 3.60-3.54 (m, 1H), 3.46–3.43(m,1H),3.43–3.40(m,1H),3.15–3.07(m,1H),2.11–2.04(m,1H),2.03–1.95(m, 1H),1.90–1.82(m,1H),1.81–1.71(m,1H).
Embodiment 13
(R) -3- (4- amino -3- (3- (3- fluorophenoxies) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- Base) piperidines -1- formonitrile HCNs
By (R) -3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidines -1- formonitrile HCNs (150mg, DMF (15mL) 0.406mmol) is dissolved in, continuously adds the fluoro- 3- of 1- (propyl- 2- alkynes -1- bases epoxide) benzene (125mg, 0.812mmol), Cuprous iodide (16mg, 0.0812mmol), triethylamine (30mg, 0.243mmol) and tetrakis triphenylphosphine palladium (24mg, 0.0203mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filtering, concentrated solvent, adds saturated common salt Water (100mL), dichloromethane (60mL × 3) extraction.Silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=22/1), obtains Oily yellow solid 40mg, yield：25.1%.
LC-MS:(pos.ion)m/z:392.16[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.31(s,1H),7.37(dd,J1=15.5Hz, J2=8.1Hz, 1H), 7.01 (d, J=11.2Hz, 1H), 6.94 (dd, J1=8.3Hz, J2=1.8Hz, 1H), 6.83 (td, J=8.4,1.9Hz, 1H),5.19(s,2H),4.85–4.76(m,1H),3.60–3.54(m,1H),3.46–3.42(m,1H),3.41–3.39(m, 1H),3.15–3.08(m,1H),2.08–2.04(m,1H),2.04–2.00(m,1H),1.88–1.82(m,1H),1.81–1.72 (m,1H).
Embodiment 14
(R) -3- (4- amino -3- (3- (3- ((3- luorobenzyls) epoxide) phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidines -1- formonitrile HCNs
By (R) -3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidines -1- formonitrile HCNs (140mg, DMF (15mL) 0.379mmol) is dissolved in, continuously adds the fluoro- 3- of 1- ((3- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) methyl) benzene (195mg, 0.758mmol), cuprous iodide (15mg, 0.0758mmol), triethylamine (30mg, 0.243mmol) and four (triphenyls Phosphine) palladium (22mg, 0.0189mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filtering, concentrated solvent, adds Enter saturated aqueous common salt (100mL), dichloromethane (60mL × 3) extraction.Silica gel thin-layer analysis isolate and purify (DCM/MeOH (v/v)= 25/1) oily yellow solid 75mg, yield, are obtained：39.7%.
LC-MS:(pos.ion)m/z:498.20[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.25(s,1H),7.42(dd,J1=14.1Hz, J2=7.7Hz, 1H), 7.29 (d, J=7.9Hz, 2H), 7.24 (d, J=8.2Hz, 1H), 7.18-7.10 (m, 1H), 6.76 (s, 1H), 6.70 (dd,J1=8.2Hz, J2=1.8Hz, 1H), 6.66 (J1=8.2Hz, J2=1.7Hz, 1H), 5.15 (s, 2H), 5.14 (s, 2H),4.84–4.76(m,1H),3.61–3.54(m,1H),3.49–3.40(m,1H),3.40–3.36(m,1H),3.16–3.07 (m,1H),2.11–2.04(m,1H),2.04–1.99(m,1H),1.88–1.83(m,1H),1.82–1.72(m,1H).
Embodiment 15
(R) -1- (3- (4- amino -3- (3- (3- ((2- luorobenzyls) epoxide) phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrazoles And [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 3- ((2- luorobenzyls) epoxide) phenol
Resorcinol (2.6g, 24mmol) is dissolved in DMF (50mL), then add Anhydrous potassium carbonate (4g, 29mmol) with adjacent fluorine bromobenzyl (1.8g, 9.5mmol), 12h is reacted at room temperature.Stop reaction, water (150mL) is added into reaction solution, is added Enter watery hydrochloric acid regulation pH to 6, ethyl acetate extraction (80mL × 3).Merge organic phase, anhydrous sodium sulfate drying, concentration, silicagel column Chromatography purifies (PE/EtOAc (v/v)=15/1), obtains pale yellow oily liquid 1.3g, yield：65%.
LC-MS:(pos.ion)m/z:219.08[M+1]+.
Step 2：The synthesis of the fluoro- 2- of compound 1- ((3- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) methyl) benzene
3- ((2- luorobenzyls) epoxide) phenol (1.3g, 6mmol) is dissolved in acetone (50mL), adds Anhydrous potassium carbonate (2.5g, 18mmol) and 3- propargyl bromides (0.92mL, 11.00mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, add Hot back flow reaction 24 hours.After reaction completely, filtering, concentration filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v)= 30/1) pale yellow oily liquid 1.25g, yield, are obtained：82%.
LC-MS:(pos.ion)m/z:257.09[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)7.55(dd,J1=7.7Hz, J2=1.3Hz, 1H), 7.42 (td, J1 =7.4Hz, J2=1.6Hz, 1H), 7.29-7.19 (m, 3H), 6.70-6.59 (m, 3H), 5.13 (s, 2H), 4.79 (d, J= 2.3Hz, 2H), 3.55 (t, J=2.3Hz, 1H)
Step 3：Compound (R) -1- (3- (4- amino -3- (3- (3- ((2- luorobenzyls) epoxide) phenoxy group) propyl- 1- alkynes - 1- yls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.301mmol) is dissolved in DMF (15mL), continuously adds the fluoro- 2- of 1- ((3- (propyl- 2- alkynes -1- bases epoxide) benzene oxygen Base) methyl) benzene (180mg, 0.602mmol), cuprous iodide (11mg, 0.0552mmol), triethylamine (17mg, 0.1657mmol) With tetrakis triphenylphosphine palladium (16mg, 0.0138mmol).Under nitrogen protections, 80 DEG C of reaction 15h are heated to, stops reaction, filters, Concentrated solvent, add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel thin-layer analysis isolates and purifies (DCM/ MeOH (v/v)=24/1), obtain oily yellow solid 83mg, yield：52.3%.
LC-MS:(pos.ion)m/z:527.22[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.24 (s, 1H), 7.56 (t, J=7.2Hz, 1H), 7.41 (d, J= 6.3Hz, 1H), 7.30-7.16 (m, 3H), 6.89-6.79 (m, 1H), 6.77 (s, 1H), 6.71 (d, J=7.5Hz, 1H), 6.68 (d, J=8.3Hz, 1H), 6.10 (dd, J1=29.2Hz, J2=16.6Hz, 1H), 5.71-5.58 (m, 1H), 5.15 (s, 2H), 5.14(s,2H),4.69–4.56(m,1H),4.55–4.44(m,0.5H),4.36–4.13(m,1H),4.09–4.01(m, 0.5H),3.65–3.53(m,0.5H),3.17–3.06(m,1H),2.93–2.82(m,0.5H),2.21–2.11(m,1H), 2.10–2.00(m,1H),1.93–1.82(m,1H),1.61–1.50(m,1H).
Embodiment 16
(R) -1- (3- (4- amino -3- (3- (2,3- difluoros phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] Pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of bis- fluoro- 3- of compound 1,2- (propyl- 2- alkynes -1- bases epoxide) benzene
2,3- difluorophenols (1g, 7.68mmol) are dissolved in acetone (30mL), addition Anhydrous potassium carbonate (3.3g, 23.06mmol) and 3- propargyl bromides (1mL, 11.53mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, be heated to reflux Reaction 24 hours.After reaction completely, filtering, concentration filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v)=100/1), Obtain pale yellow oily liquid 1g, yield：77.3%.1H NMR(400MHz,DMSO-d6):δ(ppm)7.21–6.97(3H,m), 4.94 (2H, d, J=2.4Hz), 3.64 (1H, t, J=2.3Hz)
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (2,3- difluoros phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (130mg, 0.3265mmol) is dissolved in DMF (15mL), continuously adds 1,2-, bis- fluoro- 3- (propyl- 2- alkynes -1- bases epoxide) benzene (110mg, 0.6529mmol), cuprous iodide (13mg, 0.065mmol), triethylamine (19mg, 0.196mmol) and four (triphenyls Phosphine) palladium (19mg, 0.016mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filtering, concentrated solvent, adds Enter saturated aqueous common salt (100mL), dichloromethane (60mL × 3) extraction.Silica gel thin-layer analysis isolate and purify (DCM/MeOH (v/v)= 22/1) oily yellow solid 43mg, yield, are obtained：30%.
LC-MS:(pos.ion)m/z:439.16[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.24 (s, 1H), 7.27 (t, J=7.6Hz, 1H), 7.21 (dd, J1 =14.7Hz, J2=6.8Hz, 1H), 7.07 (dd, J1=16.4Hz, J2=8.6Hz, 1H), 6.85-6.68 (m, 1H), 6.15- 6.03(m,1H),5.73–5.57(m,1H),5.30(s,2H),4.70–4.57(m,1H),4.55–4.47(m,0.5H),4.31– 4.12(m,1H),4.10–4.02(m,0.5H),3.65–3.54(m,0.5H),3.19–3.07(m,1H),2.95–2.86(m, 0.5H),2.21–2.12(m,1H),2.11–2.02(m,1H),1.93–1.82(m,1H),1.61–1.51(m,1H).
Embodiment 17
(R) (4- amino -3- (3- (4- (benzyloxy) phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] are phonetic by -3- Pyridine -1- bases) piperidines -1- formonitrile HCNs
Step 1：The synthesis of compound 4- (benzyloxy) phenol
Hydroquinones (2.4g, 22mmol) is dissolved in DMF (50mL), then add Anhydrous potassium carbonate (3.7g, 26mmol) with bromobenzyl (1.5g, 8.8mmol), 10h is reacted at room temperature.Stop reaction, into reaction solution plus water (100mL), addition are dilute For salt acid for adjusting pH to 3, ethyl acetate extracts (80mL × 3).Merge organic phase, anhydrous sodium sulfate drying, concentration, silica gel column chromatography (PE/EtOAc (v/v)=15/1) is isolated and purified, obtains pale yellow oily liquid 930mg, yield：55%.
LC-MS:(pos.ion)m/z:201.08[M+1]+.
Step 2：The synthesis of compound 1- (benzyloxy) -4- (propyl- 2- alkynes -1- bases epoxide) benzene
4- (benzyloxy) phenol (930mg, 4.645mmol) is dissolved in acetone (50mL), addition Anhydrous potassium carbonate (2g, 13.94mmol) and 3- propargyl bromides (0.75mL, 8.36mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, heat back Stream reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v)=70/ are concentrated 1) white solid 900mg, yield, are obtained：80%.LC-MS:(pos.ion)m/z:239.10[M+1]+.
Step 3：Compound (R) -3- (4- amino -3- (3- (4- (benzyloxy) phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidines -1- formonitrile HCNs synthesis
By (R) -3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidines -1- formonitrile HCNs (130mg, 0.352mmol) be dissolved in DMF (15mL), continuously add 1- (benzyloxy) -4- (propyl- 2- alkynes -1- bases epoxide) benzene (170mg, 0.704mmol), cuprous iodide (14mg, 0.0704mmol), triethylamine (21mg, 0.211mmol) and tetrakis triphenylphosphine palladium (21mg,0.0176mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filtering, concentrated solvent, adds full With saline solution (100mL), dichloromethane (50mL × 3) extraction.Silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=24/ 1) oily yellow solid 52mg, yield, are obtained：30.8%.
LC-MS:(pos.ion)m/z:480.21[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.25 (s, 1H), 7.44 (d, J=7.3Hz, 2H), 7.39 (t, J= 7.5Hz, 2H), 7.32 (t, J=7.3Hz, 1H), 7.07-7.01 (m, 2H), 7.01-6.94 (m, 2H), 5.09 (s, 2H), 5.05 (s,2H),4.86–4.74(m,1H),3.62–3.53(m,1H),3.48–3.40(m,1H),3.41–3.36(m,1H),3.17– 3.08(m,1H),2.10–2.05(m,1H),2.04–2.01(m,1H),1.89–1.83(m,1H),1.83–1.72(m,1H).
Embodiment 18
(R) -4- ((3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl-s 2- alkynes -1- bases) epoxide)-N- (3- fluorophenyls) benzamide
Step 1：The synthesis of compound N-(3- fluorophenyls) -4- hydroxybenzamides
P-hydroxybenzoic acid (1g, 7.24mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (50mL), then adds 3- fluorobenzene Amine (0.8mL, 7.96mmol, 1.56g/mL) and phosphorus tribromide (0.6mL, 5.79mmol, 2.88g/mL), under nitrogen protection, add Hot back flow reaction 5h.Stop reaction, concentrated solvent, water (120mL) is heated into reaction solution, add watery hydrochloric acid regulation pH to 3, second Acetoacetic ester extracts (60mL × 3).Merge organic phase, anhydrous sodium sulfate drying, concentration, silica gel column chromatography separating purification (DCM/ MeOH (v/v)=70/1), obtain white solid 1.01g, yield：59%.
LC-MS:(pos.ion)m/z:232.07[M+1]+.
Step 2：The synthesis of compound N-(3- fluorophenyls) -4- (propyl- 2- alkynes -1- bases epoxide) benzamide
N- (3- fluorophenyls) -4- hydroxybenzamides (1g, 4.0mmol) are dissolved in acetone (50mL), add anhydrous carbon Sour potassium (2g, 10mmol) and 3- propargyl bromides (0.7mL, 8.01mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, add Hot back flow reaction 24 hours.After reaction completely, filtering, concentration filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v)= 8/1) weak yellow liquid 0.9g, yield, are obtained：90%.
LC-MS:(pos.ion)m/z:270.09[M+1]+.
Step 3：Compound (R) -4- ((3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] Pyrimidin-3-yl) propyl- 2- alkynes -1- bases) epoxide) and-N- (3- fluorophenyls) benzamide synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (140mg, 0.351mmol) is dissolved in DMF (15mL), continuously adds N- (3- fluorophenyls) -4- (propyl- 2- alkynes -1- bases epoxide) Benzamide (190mg, 0.703mmol), cuprous iodide (14mg, 0.0703mmol), triethylamine (21mg, 0.21mmol) and four (triphenylphosphine) palladium (21mg, 0.0175mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentration Solvent, add saturated aqueous common salt (100mL), dichloromethane (150mL) extraction.Silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/ V)=24/1), oily yellow solid 68mg, yield are obtained：35.8%.
LC-MS:(pos.ion)m/z:540.21[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 10.30 (s, 1H), 8.26 (s, 1H), 7.99 (d, J=8.5Hz, 2H), 7.75 (d, J=11.7Hz, 1H), 7.55 (d, J=8.0Hz, 1H), 7.38 (dd, J1=15.2Hz, J2=7.8Hz, 1H), 7.25 (d, J=8.4Hz, 2H), 6.92 (t, J=7.5Hz, 1H), 6.84 (dd, J1=16.0Hz, J2=10.7Hz, 1H), 6.83–6.64(m,1H),6.18–6.01(m,1H),5.73–5.55(m,1H),5.28(s,2H),4.71–4.55(m,1H), 4.55–4.44(m,0.5H),4.33–4.10(m,1H),4.10–3.98(m,0.5H),3.65–3.54(m,0.5H),3.18– 3.05(m,1H),2.98–2.85(m,0.5H),2.21–2.10(m,1H),2.09–2.01(m,1H),1.92–1.82(m,1H), 1.63–1.48(m,1H).
Embodiment 19
(R) -1- (3- (4- amino -3- (3- ((3- fluorophenyls) amino) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] Pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of the fluoro- N- of compound 3- (propyl- 2- alkynes -1- bases) aniline
M-fluoroaniline (1.2g, 11.0mmol) is dissolved in ethanol (40mL), addition natrium carbonicum calcinatum (1.4g, 13.0mmol) and 3- propargyl bromides (1.1mL, 13.0mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, be heated to reflux Reaction 24 hours.After reaction completely, filtering, concentration filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v)=70/1), Obtain white liquid 450mg, yield：20%.
LC-MS:(pos.ion)m/z:150.06[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- ((3- fluorophenyls) amino) propyl- 1- alkynes -1- bases) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (130mg, 0.326mmol) is dissolved in DMF (15mL), continuously add the fluoro- N- of 3- (propyl- 2- alkynes -1- bases) aniline (100mg, 0.652mmol), cuprous iodide (14mg, 0.0703mmol), triethylamine (21mg, 0.21mmol) and tetrakis triphenylphosphine palladium (21mg,0.0175mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filtering, concentrated solvent, adds full With saline solution (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=35/ 1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=22/1), obtains oily yellow solid 80mg, produces Rate：58.4%.
LC-MS:(pos.ion)m/z:420.19[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)DMSO-d6):δ(ppm)8.22(s,1H),7.14(dd,J1= 15.4Hz,J2=8.0Hz, 1H), 6.86-6.67 (m, 1H), 6.56 (d, J=6.5Hz, 1H), 6.54 (d, J=2.0Hz, 1H), 6.49 (t, J=6.1Hz, 1H), 6.40 (dd, J1=11.9Hz, J2=4.9Hz, 1H), 6.16-6.02 (m, 1H), 5.72-5.57 (m, 1H), 4.70-4.55 (m, 1H), 4.52-4.47 (m, 0.5H), 4.26 (d, J=6.2Hz, 2H), 4.21-4.08 (m, 1H), 4.07–4.01(m,0.5H),3.63–3.52(m,0.5H),3.17–3.05(m,1H),2.93–2.83(m,0.5H),2.22– 2.11(m,1H),2.09–1.99(m,1H),1.92–1.82(m,1H),1.60–1.49(m,1H).
Embodiment 20
(R) -1- (3- (4- amino -3- (3- (3- ((4- luorobenzyls) epoxide) phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrazoles And [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 3- ((4- luorobenzyls) epoxide) phenol
Resorcinol (2.1g, 19.0mmol) is dissolved in DMF (50mL), then add Anhydrous potassium carbonate (4.0g, 29.0mmol) and to fluorine bromobenzyl (1.8g, 9.5mmol), 12h is reacted at room temperature.Stop reaction, concentrated solvent, add into reaction solution Water (150mL), add watery hydrochloric acid regulation pH to 3, ethyl acetate extraction (60mL × 3).Merge organic phase, anhydrous sodium sulfate is done It is dry, concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=12/1), obtain pale yellow oily liquid 1.24g, yield： 59%.
LC-MS:(pos.ion)m/z:219.08[M+1]+.
Step 2：The synthesis of compound 1- ((4- luorobenzyls) epoxide) -3- (propyl- 2- alkynes -1- bases epoxide) benzene
3- ((4- luorobenzyls) epoxide) phenol (1.22g, 5.59mmol) is dissolved in acetone (50mL), adds Carbon Dioxide Potassium (2.34g, 16.8mmol) and 3- propargyl bromides (0.88mL, 10.1mmol, 1.38g/mL).Replace nitrogen three times, nitrogen protection Under, heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/ are concentrated V)=30/1), weak yellow liquid 1.17g, yield are obtained：86%.
LC-MS:(pos.ion)m/z:257.09[M+1]+.
Step 3：Compound (R) -1- (3- (4- amino -3- (3- (3- ((4- luorobenzyls) epoxide) phenoxy group) propyl- 1- alkynes - 1- yls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.301mmol) is dissolved in DMF (15mL), continuously adds 1- ((4- luorobenzyls) epoxide) -3- (propyl- 2- alkynes -1- bases Epoxide) benzene (154mg, 0.602mmol), cuprous iodide (12mg, 0.060mmol), triethylamine (19mg, 0.18mmol) and four (triphenylphosphine) palladium (18mg, 0.015mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentration Solvent, add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v) crude product=35/1), is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=22/1), obtains oil yellow color and consolidate Body 48mg, yield：30.2%.
LC-MS:(pos.ion)m/z:527.21[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.24 (s, 1H), 7.50 (d, J=5.7Hz, 1H), 7.49 (d, J= 5.7Hz, 1H), 7.24 (t, J=8.2Hz, 1H), 7.19 (t, J=8.8Hz, 2H), 6.89-6.79 (m, 1H), 6.75 (d, J= 2.1Hz,1H),6.69(dd,J1=8.2Hz, J2=1.9Hz, 1H), 6.66 (dd, J1=8.2Hz, J2=1.9Hz, 1H), 6.16–6.03(m,1H),5.73–5.57(m,1H),5.14(s,2H),5.09(s,2H),4.69–4.58(m,1H),4.55– 4.46(m,0.5H),4.30–4.13(m,1H),4.08–4.02(m,0.5H),3.63–3.54(m,0.5H),3.16–3.06(m, 1H),2.92–2.84(m,0.5H),2.21–2.11(m,1H),2.11–2.02(m,1H),1.92–1.83(m,1H),1.59– 1.50(m,1H).
Embodiment 21
(R) -1- (3- (4- amino -3- (3- (5- (benzyloxy) -2- fluorophenoxies) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of the fluoro- 3- of compound 4- (propyl- 2- alkynes -1- bases epoxide) phenol
4- fluorine resorcinol (1.62g, 12.60mmol) is dissolved in acetone (50mL), then adds Anhydrous potassium carbonate (3.52g, 25.21mmol) and 3- propargyl bromides (0.87mL, 8.40mmol, 1.38g/mL).Replace nitrogen three times, nitrogen protection Under, heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/ are concentrated V)=20/1), weak yellow liquid 850mg, yield are obtained：51%.
LC-MS:(pos.ion)m/z:167.04[M+1]+.
Step 2：The synthesis of the fluoro- 2- of compound 4- (benzyloxy) -1- (propyl- 2- alkynes -1- bases epoxide) benzene
The fluoro- 3- of 4- (propyl- 2- alkynes -1- bases epoxide) phenol (850mg, 5.115mmol) is dissolved in and is dissolved in DMF (50mL) In, Anhydrous potassium carbonate (2.2g, 15.348mmol) and bromobenzyl (0.8mL, 6.139mmol, 1.44g/mL) are then added, room temperature is anti- Answer 12h.Stop reaction, concentrated solvent, into reaction solution plus water (150mL), ethyl acetate extract (60mL × 3).Merge organic Phase, anhydrous sodium sulfate drying, concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=80/1), obtain faint yellow oily Liquid 1g, yield：76.27%.
LC-MS:(pos.ion)m/z:257.09[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 7.46 (d, J=7.4Hz, 2H), 7.40 (t, J=7.6Hz, 2H), 7.34 (t, J=7.3Hz, 1H), 7.15 (dd, J1=11.2Hz, J2=8.9Hz, 1H), 6.92 (dd, J1=7.2Hz, J2= 2.9Hz,1H),6.61(dt,J1=8.9Hz, J2=3.1Hz, 1H), 5.07 (s, 2H), 4.89 (d, J=2.4Hz, 2H), 3.62 (t, J=2.4Hz, 1H)
Step 3：Compound (R) -1- (3- (4- amino -3- (3- (5- (benzyloxy) -2- fluorophenoxies) propyl- 1- alkynes -1- Base) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (130mg, 0.326mmol) is dissolved in DMF (15mL), continuously adds the fluoro- 2- of 4- (benzyloxy) -1- (propyl- 2- alkynes -1- base oxygen Base) benzene (170mg, 0.653mmol), cuprous iodide (13mg, 0.065mmol), triethylamine (20mg, 0.196mmol) and four (three Phenylphosphine) palladium (19mg, 0.0163mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentration is molten Agent, add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/ V)=30/1), crude product is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=15/1), obtains oily yellow solid 44mg, yield：25.5%.
LC-MS:(pos.ion)m/z:527.21[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.25(s,1H),7.65–7.40(m,2H),7.39–7.31(m, 2H),7.31–7.24(m,1H),7.22–7.13(m,1H),7.09(s,1H),6.86–6.69(m,1H),6.62(s,1H), 6.18–5.99(m,1H),5.74–5.54(m,1H),5.25(s,2H),5.09(s,2H),4.79–4.56(m,1H),4.55– 4.44(m,0.5H),4.33–4.11(m,1H),4.09–3.94(m,0.5H),3.62–3.55(m,0.5H),3.16–3.05(m, 1H),2.93–2.81(m,0.5H),2.23–2.10(m,1H),2.11–1.98(m,1H),1.94–1.80(m,1H),1.62– 1.48(m,1H).
Embodiment 22
(R) -1- (3- (4- amino -3- (3- (3- (benzyloxy) -4- fluorophenoxies) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 3- (benzyloxy) -4- fluorophenols
4- fluorine resorcinol (1.7g, 13mmol) is dissolved in and is dissolved in DMF (50mL), then adds Anhydrous potassium carbonate (3.7g, 26mmol) and bromobenzyl (1mL, 8.8mmol, 1.44g/mL), react at room temperature 10h.Stop reaction, concentrated solvent, to anti- Answer and add water (150mL) in liquid, pH to 3 is adjusted with appropriate watery hydrochloric acid.Ethyl acetate extracts (60mL × 3).Merge organic phase, nothing Aqueous sodium persulfate is dried, and concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=20/1), obtains pale yellow oily liquid 930mg, yield：55%.
LC-MS:(pos.ion)m/z:219.07[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)9.37(1H,s),7.48–7.30(m,5H),6.98(dd,J1= 11.4Hz,J2=8.8Hz, 1H), 6.60 (dd, J1=7.3Hz, J2=2.7Hz, 1H), 6.29 (dt, J1=8.7Hz, J2= 3.1Hz,1H),5.11(s,2H).
Step 2：The synthesis of the fluoro- 4- of compound 2- (benzyloxy) -1- (propyl- 2- alkynes -1- bases epoxide) benzene
3- (benzyloxy) -4- fluorophenols (800mg, 3.66mmol) are dissolved in acetone (35mL), then added anhydrous Potassium carbonate (1.6g, 11mmol) and 3- propargyl bromides (0.4mL, 4.4mmol, 1.38g/mL).Replace nitrogen three times, nitrogen protection Under, heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/ are concentrated V)=70/1), weak yellow liquid 650mg, yield are obtained：71.3%.
LC-MS:(pos.ion)m/z:257.09[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 7.47 (d, J=7.5Hz, 2H), 7.41 (t, J=7.5Hz, 2H), 7.35 (t, J=7.3Hz, 1H), 7.16 (dd, J1=11.2Hz, J2=9.0Hz, 1H), 6.90 (dd, J1=7.2Hz, J2= 2.9Hz,1H),6.55(dt,J1=8.9Hz, J2=3.1Hz, 1H), 5.17 (s, 2H), 4.77 (d, J=2.4Hz, 2H), 3.56 (t, J=2.4Hz, 1H)
Step 3：Compound (R) -1- (3- (4- amino -3- (3- (3- (benzyloxy) -4- fluorophenoxies) propyl- 1- alkynes -1- Base) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (130mg, 0.326mmol) is dissolved in DMF (15mL), continuously adds the fluoro- 4- of 2- (benzyloxy) -1- (propyl- 2- alkynes -1- base oxygen Base) benzene (170mg, 0.652mmol), cuprous iodide (13mg, 0.065mmol), triethylamine (20mg, 0.195mmol) and four (three Phenylphosphine) palladium (19mg, 0.016mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentration is molten Agent, add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/ V)=30/1), crude product is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=18/1), obtains oily yellow solid 50mg, yield：29.0%.
LC-MS:(pos.ion)m/z:527.21[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.25 (s, 1H), 7.45 (d, J=6.1Hz, 2H), 7.41-7.34 (m, 2H), 7.32 (s, 1H), 7.18 (t, J=9.6Hz, 1H), 6.99 (d, J=3.7Hz, 1H), 6.88-6.77 (m, 1H), 6.67 (d, J=7.0Hz, 2H), 6.17-6.03 (m, 1H), 5.73-5.55 (m, 1H), 5.19 (s, 2H), 5.14 (s, 2H), 4.70–4.56(m,1H),4.55–4.44(m,0.5H),4.31–4.11(m,1H),4.09–3.99(m,0.5H),3.65–3.53 (m,0.5H),3.16–3.06(m,1H),2.95–2.83(m,0.5H),2.21–2.11(m,1H),2.10–2.00(m,1H), 1.94–1.80(m,1H),1.61–1.50(m,1H).
Embodiment 23
(R) -1- (3- (4- amino -3- (3- (the chloro- 4- fluorophenoxies of 3-) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] Pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of the fluoro- 4- of the chloro- 1- of compound 2- (propyl- 2- alkynes -1- bases epoxide) benzene
The chloro- 4- fluorophenols (1g, 6.8236mmol) of 3- are dissolved in acetone (40mL), then add Anhydrous potassium carbonate (2.9g, 20.471mmol) and 3- propargyl bromides (0.75mL, 8.183mmol, 1.38g/mL).Replace nitrogen three times, nitrogen protection Under, heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/ are concentrated V)=60/1), weak yellow liquid 1.1g, yield are obtained：87%..
LC-MS:(pos.ion)m/z:185.01[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (the chloro- 4- fluorophenoxies of 3-) propyl- 1- alkynes -1- bases) -1H- Pyrazolo [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.3014mmol) is dissolved in DMF (15mL), continuously adds the fluoro- 4- of the chloro- 1- of 2- (propyl- 2- alkynes -1- bases epoxide) benzene (120mg, 0.6027mmol), cuprous iodide (13mg, 0.065mmol), triethylamine (18mg, 0.1808mmol) and four (triphens Base phosphine) palladium (19mg, 0.016mmol).Under nitrogen protections, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentrated solvent, Add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v) =35/1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=20/1), obtains oily yellow solid 41mg, yield：29.9%.
LC-MS:(pos.ion)m/z:455.13[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.24 (s, 1H), 7.40 (t, J=6.0Hz, 1H), 7.38 (dd, J1 =6.0Hz, J2=3.0Hz, 1H), 7.12 (dt, J=8.8,3.2Hz, 1H), 6.85-6.69 (m, 1H), 6.16-6.02 (m, 1H),5.73–5.56(m,1H),5.19(s,2H),4.69–4.58(m,1H),4.54–4.46(m,0.5H),4.30–4.13(m, 1H),4.09–4.00(m,0.5H),3.63–3.55(m,0.5H),3.19–3.07(m,1H),2.94–2.87(m,0.5H), 2.21–2.12(m,1H),2.10–2.02(m,1H),1.93–1.83(m,1H),1.61–1.50(m,1H).
Embodiment 24
(R) -1- (3- (4- amino -3- (3- (the chloro- 5- fluorophenoxies of 3-) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] Pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of the fluoro- 5- of the chloro- 3- of compound 1- (propyl- 2- alkynes -1- bases epoxide) benzene
The chloro- 5- fluorophenols (1g, 6.8236mmol) of 3- are dissolved in acetone (35mL), then add Anhydrous potassium carbonate (2.9g, 20.471mmol) and 3- propargyl bromides (0.75mL, 8.188mmol, 1.38g/mL).Replace nitrogen three times, nitrogen protection Under, heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/ are concentrated V)=60/1), weak yellow liquid 1.12g, yield are obtained：84.7%.
LC-MS:(pos.ion)m/z:185.01[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (the chloro- 5- fluorophenoxies of 3-) propyl- 1- alkynes -1- bases) -1H- Pyrazolo [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.301mmol) is dissolved in DMF (15mL), continuously adds the fluoro- 5- of the chloro- 3- of 1- (propyl- 2- alkynes -1- bases epoxide) benzene (120mg, 0.6027mmol), cuprous iodide (13mg, 0.065mmol), triethylamine (18mg, 0.1808mmol) and four (triphens Base phosphine) palladium (19mg, 0.016mmol).Under nitrogen protections, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentrated solvent, Add saturated aqueous common salt (80mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v)= 40/1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=20/1), obtains oily yellow solid 20mg, Yield：14.5%.
LC-MS:(pos.ion)m/z:455.13[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.25 (s, 1H), 7.11 (s, 1H), 7.08 (d, J=32.3Hz, 2H),6.87–6.69(m,1H),6.16–6.01(m,1H),5.74–5.55(m,1H),5.23(s,2H),4.75–4.57(m, 1H),4.54–4.45(m,0.5H),4.30–4.12(m,1H),4.11–4.01(m,0.5H),3.67–3.53(m,0.5H), 3.17–3.06(m,1H),2.97–2.85(m,0.5H),2.22–2.12(m,1H),2.11–2.01(m,1H),1.93–1.84 (m,1H),1.61–1.50(m,1H).
Embodiment 25
(R) -4- ((3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl-s 2- alkynes -1- bases) epoxide) -2- (benzyloxy) benzonitrile
Step 1：The synthesis of compound 2- (benzyloxy) -4- hydroxy-phenylformonitriles
2,4- dihydroxy cyanophenyl (1.5g, 11mmol) is dissolved in and is dissolved in DMF (50mL), then adds Anhydrous potassium carbonate (3.7g, 26mmol) and bromobenzyl (1mL, 8.8mmol, 1.44g/mL), react at room temperature 10h.Stop reaction, concentrated solvent, to anti- Answer and add water (150mL) in liquid, pH to 3 is adjusted with appropriate watery hydrochloric acid.Ethyl acetate extracts (60mL × 3).Merge organic phase, nothing Aqueous sodium persulfate is dried, and concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=6/1), obtains yellow oily liquid 1.1g, yield：58%.
LC-MS:(pos.ion)m/z:226.08[M+1]+.
Step 2：The synthesis of compound 2- (benzyloxy) -4- (propyl- 2- alkynes -1- bases epoxide) benzonitrile
2- (benzyloxy) -4- hydroxy-phenylformonitriles (800mg, 3.552mmol) are dissolved in acetone (30mL), then added Anhydrous potassium carbonate (1.5g, 10.66mmol) and 3- propargyl bromides (0.4mL, 4.263mmol, 1.38g/mL).Replace nitrogen three times, Under nitrogen protection, heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/ are concentrated EtOAc (v/v)=15/1), obtain weak yellow liquid 560mg, yield：59.8%.
LC-MS:(pos.ion)m/z:264.09[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)7.68(dd,J1=8.5Hz, J2=5.4Hz, 1H), 7.48 (d, J =7.4Hz, 2H), 7.42 (t, J=7.6Hz, 2H), 7.36 (t, J=7.3Hz, 1H), 6.92 (d, J=2.1Hz, 1H), 6.73 (dd,J1=8.6Hz, J2=2.1Hz, 1H), 5.27 (s, 2H), 4.92 (d, J=2.2Hz, 2H), 3.64 (t, J=2.2Hz, 1H).
Step 3：Compound (R) -4- ((3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] Pyrimidin-3-yl) propyl- 2- alkynes -1- bases) epoxide) and -2- (benzyloxy) benzonitrile synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (130mg, 0.326mmol) is dissolved in DMF (15mL), continuously adds 2- (benzyloxy) -4- (propyl- 2- alkynes -1- bases epoxide) benzene Formonitrile HCN (170mg, 0.652mmol), cuprous iodide (13mg, 0.065mmol), triethylamine (20mg, 0.195mmol) and four (three Phenylphosphine) palladium (19mg, 0.016mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentration is molten Agent, add saturated aqueous common salt (80mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/ V)=30/1), crude product is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=18/1), obtains oily yellow solid 34mg, yield：19.5%.
LC-MS:(pos.ion)m/z:534.22[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.25 (s, 1H), 7.73 (d, J=8.5Hz, 1H), 7.48 (d, J= 7.0Hz, 2H), 7.39 (s, 2H), 7.33 (d, J=5.7Hz, 1H), 7.04 (s, 1H), 6.87 (d, J=8.4Hz, 1H), 6.80- 6.60(m,1H),6.19–5.99(m,1H),5.74–5.56(m,1H),5.30(s,2H),5.28(s,2H),4.70–4.58(m, 1H),4.54–4.46(m,0.5H),4.28–4.12(m,1H),4.09–3.99(m,0.5H),3.62–3.54(m,0.5H), 3.17–3.06(m,1H),2.94–2.85(m,0.5H),2.20–2.11(m,1H),2.11–2.02(m,1H),1.93–1.83 (m,1H),1.61–1.49(m,1H).
Embodiment 26
(R) -2- ((3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl-s 2- alkynes -1- bases) epoxide) -4- (benzyloxy) benzonitrile
Step 1：The synthesis of compound 4-hydroxy base -2- (propyl- 2- alkynes -1- bases epoxide) benzonitrile
2,4- dihydroxy cyanophenyl (2g, 14.8mmol) is dissolved in acetone (50mL), then adds Anhydrous potassium carbonate (4.2g, 30mmol) and 3- propargyl bromides (0.87mL, 10mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, heating Back flow reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v)=7/ are concentrated 1) weak yellow liquid 450mg, yield, are obtained：26%.LC-MS:(pos.ion)m/z:174.05[M+1]+.
Step 2：The synthesis of compound 4- (benzyloxy) -2- (propyl- 2- alkynes -1- bases epoxide) benzonitrile
4- hydroxyls -2- (propyl- 2- alkynes -1- bases epoxide) benzonitrile (450mg, 2.5986mmol) is dissolved in and is dissolved in DMF In (30mL), Anhydrous potassium carbonate (1.1g, 7.7958mmol) and bromobenzyl (0.4mL, 3.11mmol, 1.44g/mL) are then added, React at room temperature 10h.Stop reaction, concentrated solvent, into reaction solution plus water (100mL), ethyl acetate extract (50mL × 3).Close And organic phase, anhydrous sodium sulfate drying, concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=8/1), obtain yellowish Color oily liquids 594mg, yield：86.8%.
LC-MS:(pos.ion)m/z:264.09[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 7.68 (d, J=8.6Hz, 1H), 7.47 (d, J=7.4Hz, 2H), 7.41 (t, J=7.5Hz, 2H), 7.36 (t, J=7.3Hz, 1H), 6.93 (d, J=2.1Hz, 1H), 6.80 (dd, J1= 8.7Hz,J2=2.1Hz, 1H), 5.20 (s, 2H), 5.00 (s, 2H), 3.66 (t, J=2.3Hz, 1H)
Step 3：Compound (R) -2- ((3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] Pyrimidin-3-yl) propyl- 2- alkynes -1- bases) epoxide) and -4- (benzyloxy) benzonitrile synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (130mg, 0.326mmol) is dissolved in DMF (15mL), continuously adds 4- (benzyloxy) -2- (propyl- 2- alkynes -1- bases epoxide) benzene Formonitrile HCN (170mg, 0.652mmol), cuprous iodide (13mg, 0.065mmol), triethylamine (20mg, 0.195mmol) and four (three Phenylphosphine) palladium (19mg, 0.016mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentration is molten Agent, add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/ V)=32/1), crude product is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=16/1), obtains oily yellow solid 33mg, yield：18.9%.
LC-MS:(pos.ion)m/z:534.22[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.25 (s, 1H), 7.71 (d, J=8.5Hz, 1H), 7.46 (d, J= 6.9Hz, 2H), 7.41-7.34 (m, 2H), 7.33 (s, 1H), 7.14 (s, 1H), 6.82 (d, J=8.5Hz, 1H), 6.80-6.63 (m,1H),6.16–6.04(m,1H),5.72–5.57(m,1H),5.36(s,2H),5.23(s,2H),4.72–4.58(m,1H), 4.55–4.47(m,0.5H),4.29–4.17(m,1H),4.10–4.00(m,0.5H),3.62–3.53(m,0.5H),3.17– 3.05(m,1H),2.91–2.80(m,0.5H),2.22–2.11(m,1H),2.10–2.02(m,1H),1.91–1.81(m,1H), 1.59–1.51(m,1H).
Embodiment 27
(R) -1- (3- (4- amino -3- (3- (3- ((3- (mesyl) benzyl) epoxide) phenoxy group) propyl- 1- alkynes -1- Base) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 3- (propyl- 2- alkynes -1- bases epoxide) phenol
Resorcinol (5.5g, 50.437mmol) is dissolved in acetone (100mL), then adds Anhydrous potassium carbonate (11g, 75.656mmol) and 3- propargyl bromides (2.2mL, 25.219mmol, 1.38g/mL).Replace nitrogen three times, nitrogen protection Under, heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/ are concentrated V)=12/1), weak yellow liquid 2.52g, yield are obtained：67%.
LC-MS:(pos.ion)m/z:149.05[M+1]+.
Step 2：The synthesis of compound 1- (mesyl) -3- ((3- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) methyl) benzene
3- (propyl- 2- alkynes -1- bases epoxide) phenol (500mg, 3.374mmol) is dissolved in and is dissolved in DMF (25mL), then Anhydrous potassium carbonate (400mg, 4.817mmol) and 3- sulfonyloxy methyl benzyl bromines (400mg, 1.605mmol) are added, reacts at room temperature 12h. Stop reaction, concentrated solvent, water (50mL), ethyl acetate extraction (30mL × 3) are added into reaction solution.Merge organic phase, nothing Aqueous sodium persulfate is dried, and concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=5/1), obtains pale yellow oily liquid 450mg, yield：88.5%.
LC-MS:(pos.ion)m/z:317.08[M+1]+.
Step 3：Compound (R) -1- (3- (4- amino -3- (3- (3- ((3- (mesyl) benzyl) epoxide) phenoxy group) Propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (130mg, 0.326mmol) is dissolved in DMF (15mL), continuously adds 1- (mesyl) -3- ((3- (propyl- 2- alkynes -1- base oxygen Base) phenoxy group) methyl) benzene (210mg, 0.652mmol), cuprous iodide (13mg, 0.065mmol), triethylamine (20mg, 0.195mmol) and tetrakis triphenylphosphine palladium (19mg, 0.016mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, are stopped Reaction, filtering, concentrated solvent, add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separates Purifying (DCM/MeOH (v/v)=35/1), obtain crude product, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=20/1), Obtain oily yellow solid 47mg, yield：24.5%.
LC-MS:(pos.ion)m/z:587.20[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.24 (s, 1H), 8.03 (s, 1H), 7.90 (d, J=7.4Hz, 1H), 7.81 (d, J=7.2Hz, 1H), 7.67 (t, J=7.4Hz, 1H), 7.27 (t, J=8.1Hz, 1H), 6.99-6.80 (m, 1H),6.79(s,1H),6.71(dd,J1=15.9Hz, J2=8.0Hz, 2H), 6.18-6.02 (m, 1H), 5.73-5.55 (m, 1H),5.24(s,2H),5.16(s,2H),4.71–4.57(m,1H),4.53–4.46(m,0.5H),4.28–4.15(m,1H), 4.09–4.01(m,0.5H),3.64–3.55(m,0.5H),3.24(s,3H),3.17–3.04(m,1H),2.94–2.83(m, 0.5H),2.21–2.12(m,1H),2.11–2.02(m,1H),1.94–1.82(m,1H),1.61–1.49(m,1H).
Embodiment 28
(R) -1- (3- (4- amino -3- (3- (3- ((3- fluorophenoxies) methyl) phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 3- ((3- fluorophenoxies) methyl) phenol
Hydroxyl benzyl bromine (500mg, 2.673mmol), which is dissolved in, by between is dissolved in DMF (30mL), then adds Anhydrous potassium carbonate (1.2g, 8.02mmol) and 3- fluorophenols (0.4mL, 4.01mmol, 1.238g/mL), react at room temperature 13h.Stop reaction, concentration Solvent, into reaction solution plus water (80mL), ethyl acetate extract (30mL × 3).Merge organic phase, anhydrous sodium sulfate drying is dense Contracting, silica gel column chromatography separating purification (PE/EtOAc (v/v)=15/1), obtains pale yellow oily liquid 300mg, yield： 51.4%.
LC-MS:(pos.ion)m/z:219.07[M+1]+.
Step 2：The synthesis of the fluoro- 3- of compound 1- ((3- (propyl- 2- alkynes -1- bases epoxide) benzyl) epoxide) benzene
3- ((3- fluorophenoxies) methyl) phenol (270mg, 1.237mmol) is dissolved in acetone (20mL), Ran Houjia Enter Anhydrous potassium carbonate (550mg, 3.712mmol) and 3- propargyl bromides (0.2mL, 1.856mmol, 1.38g/mL).Replace nitrogen three It is secondary, under nitrogen protection, heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification are concentrated (PE/EtOAc (v/v)=50/1), obtains colourless liquid 251mg, yield：79.1%.
LC-MS:(pos.ion)m/z:257.09[M+1]+；
1H NMR(400MHz,DMSO-d6):δ (ppm) 7.36-7.30 (2H, m), 7.06 (2H, d, J=7.5Hz), 6.99- 6.95(1H,m),6.92–6.85(2H,m),6.77(1H,td,J1=8.3Hz, J2=2.0Hz), 5.10 (2H, s), 4.81 (2H, D, J=2.3Hz), 3.56 (1H, t, J=2.3Hz)
Step 3：Compound (R) -1- (3- (4- amino -3- (3- (3- ((3- fluorophenoxies) methyl) phenoxy group) propyl- 1- Alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (140mg, 0.3516mmol) is dissolved in DMF (15mL), continuously adds the fluoro- 3- of 1- ((3- (propyl- 2- alkynes -1- bases epoxide) benzyls Base) epoxide) benzene (250mg, 0.703mmol), cuprous iodide (14mg, 0.0703mmol), triethylamine (21mg, 0.210mmol) With tetrakis triphenylphosphine palladium (21mg, 0.0175mmol).Under nitrogen protections, 80 DEG C of reaction 15h are heated to, stops reaction, filters, Concentrated solvent, add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/ MeOH (v/v)=40/1), crude product is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=20/1), obtains oil yellow Color solid 60mg, yield：32.4%.
LC-MS:(pos.ion)m/z:527.21[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.25(s,1H),7.37(s,1H),7.28(s,1H),7.19(s, 1H), 7.08 (d, J=5.9Hz, 2H), 6.87 (dd, J1=19.8Hz, J2=9.3Hz, 3H), 6.79-6.72 (m, 1H), 6.19- 6.00(m,1H),5.74–5.58(m,1H),5.18(s,2H),5.12(s,2H),4.75–4.56(m,1H),4.55–4.46(m, 0.5H),4.37–4.12(m,1H),4.13–3.98(m,0.5H),3.67–3.52(m,0.5H),3.20–3.06(m,1H), 2.94–2.82(m,0.5H),2.22–2.12(m,1H),2.10–1.96(m,1H),1.92–1.82(m,1H),1.63–1.48 (m,1H).
Embodiment 29
(R) -1- (3- (4- amino -3- (3- (3- (phenoxymethyl) phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 3- (phenoxymethyl) phenol
Hydroxyl benzyl bromine (500mg, 2.673mmol), which is dissolved in, by between is dissolved in DMF (30mL), then adds Anhydrous potassium carbonate (1.2g, 8.6mmol) and phenol (400mg, 4.01mmol), react at room temperature 30h.Stop reaction, concentrated solvent, into reaction solution Add water (80mL), ethyl acetate extraction (30mL × 3).Merge organic phase, anhydrous sodium sulfate drying, concentration, silica gel column chromatography point From purifying (PE/EtOAc (v/v)=15/1), pale yellow oily liquid 270mg, yield are obtained：50.45%.
LC-MS:(pos.ion)m/z:201.08[M+1]+.
Step 2：The synthesis of compound 1- (phenoxymethyl) -3- (propyl- 2- alkynes -1- bases epoxide) benzene
3- (phenoxymethyl) phenol (200mg, 0.99mmol) is dissolved in acetone (25mL), then adds anhydrous carbon Sour potassium (420mg, 2.997mmol) and 3- propargyl bromides (0.18mL, 1.499mmol, 1.38g/mL).Replace nitrogen three times, nitrogen Under protection, heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/ are concentrated EtOAc (v/v)=50/1), obtain colourless liquid 141mg, yield：59.2%.
LC-MS:(pos.ion)m/z:239.10[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)7.31(ddd,J1=12.2Hz, J2=10.3Hz, J3=7.6Hz, 3H), 7.06 (d, J=6.9Hz, 2H), 7.01 (d, J=8.0Hz, 2H), 6.95 (q, J=7.0Hz, 2H), 5.08 (s, 2H), 4.80 (d, J=2.3Hz, 2H), 3.56 (t, J=2.3Hz, 1H)
Step 3：Compound (R) -1- (3- (4- amino -3- (3- (3- (phenoxymethyl) phenoxy group) propyl- 1- alkynes -1- Base) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (80mg, 0.200mmol) is dissolved in DMF (15mL), continuously adds 1- (phenoxymethyl) -3- (propyl- 2- alkynes -1- bases epoxide) Benzene (145mg, 0.4018mmol), cuprous iodide (8mg, 0.040mmol), triethylamine (12mg, 0.1205mmol) and four (triphens Base phosphine) palladium (12mg, 0.010mmol).Under nitrogen protections, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentrated solvent, Add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v) =35/1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=20/1), obtains oily yellow solid 43mg, yield：42.08%.
LC-MS:(pos.ion)m/z:509.22[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.24 (s, 1H), 7.36 (t, J=7.8Hz, 1H), 7.25 (s, 2H), 7.18 (s, 1H), 7.08 (t, J=7.1Hz, 2H), 7.00 (d, J=7.9Hz, 2H), 6.91 (t, J=6.9Hz, 1H), 6.87–6.66(m,1H),6.16–6.02(m,1H),5.73–5.55(m,1H),5.18(s,2H),5.10(s,2H),4.72– 4.58(m,1H),4.55–4.48(m,0.5H),4.34–4.14(m,1H),4.09–4.02(m,0.5H),3.63–3.54(m, 0.5H),3.17–3.06(m,1H),2.92–2.85(m,0.5H),2.22–2.12(m,1H),2.10–2.03(m,1H),1.94– 1.82(m,1H),1.60–1.50(m,1H).
Embodiment 30
(R) -1- (3- (4- amino -3- (3- (2,4 difluorobenzene epoxide) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] Pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of bis- fluoro- 1- of compound 2,4- (propyl- 2- alkynes -1- bases epoxide) benzene
2,4- difluorophenols (1g, 7.687mmol) are dissolved in acetone (25mL), then add Anhydrous potassium carbonate (3.2g, 23.06mmol) and 3- propargyl bromides (1mL, 9.224mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, add Hot back flow reaction 24 hours.After reaction completely, filtering, concentration filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v)= 80/1) weak yellow liquid 1.2g, yield, are obtained：93%.LC-MS:(pos.ion)m/z:169.04[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (2,4 difluorobenzene epoxide) propyl- 1- alkynes -1- bases) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.3014mmol) is dissolved in DMF (15mL), continuously adds 2,4-, bis- fluoro- 1- (propyl- 2- alkynes -1- bases epoxide) benzene (105mg, 0.6027mmol), cuprous iodide (12mg, 0.0602mmol), triethylamine (18mg, 0.1808mmol) and four (triphens Base phosphine) palladium (18mg, 0.015mmol).Under nitrogen protections, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentrated solvent, Add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v) =32/1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=18/1), obtains oily yellow solid 32mg, yield：24.2%.
LC-MS:(pos.ion)m/z:439.16[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.25(s,1H),7.44(dd,J1=14.1Hz, J2=8.9Hz, 1H),7.35(dd,J1=14.3Hz, J2=5.6Hz, 1H), 7.09 (t, J=7.6Hz, 1H), 6.88-6.66 (m, 1H), 6.18- 6.01(m,1H),5.75–5.56(m,1H),5.24(s,2H),4.74–4.58(m,1H),4.55–4.46(m,0.5H),4.35– 4.14(m,1H),4.11–4.02(m,0.5H),3.65–3.56(m,0.5H),3.20–3.07(m,1H),2.95–2.86(m, 0.5H),2.23–2.12(m,1H),2.11–2.03(m,1H),1.94–1.81(m,1H),1.62–1.49(m,1H).
Embodiment 31
(R) -1- (3- (4- amino -3- (3- (2,5- difluoros phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] Pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of bis- fluoro- 2- of compound 1,4- (propyl- 2- alkynes -1- bases epoxide) benzene
2,5- difluorophenols (1g, 7.687mmol) are dissolved in acetone (35mL), then add Anhydrous potassium carbonate (3.2g, 23.06mmol) and 3- propargyl bromides (1mL, 9.224mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, add Hot back flow reaction 24 hours.After reaction completely, filtering, concentration filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v)= 80/1) weak yellow liquid 1.25g, yield, are obtained：96.7%.LC-MS:(pos.ion)m/z:169.04[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (2,5- difluoros phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.3014mmol) is dissolved in DMF (15mL), continuously adds the fluoro- 2- of Isosorbide-5-Nitrae-two (propyl- 2- alkynes -1- bases epoxide) benzene (105mg, 0.6027mmol), cuprous iodide (12mg, 0.0602mmol), triethylamine (18mg, 0.1808mmol) and four (triphens Base phosphine) palladium (18mg, 0.0150mmol).Under nitrogen protections, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentrated solvent, Add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v) =38/1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=20/1), obtains oily yellow solid 31mg, yield：23.4%.
LC-MS:(pos.ion)m/z:439.16[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.25(s,1H),7.45–7.36(m,1H),7.36–7.28(m, 1H), 6.84 (t, J=8.4Hz, 1H), 6.76-6.64 (m, 1H), 6.17-6.02 (m, 1H), 5.72-5.57 (m, 1H), 5.28 (s,2H),4.71–4.58(m,1H),4.54–4.47(m,0.5H),4.29–4.15(m,1H),4.08–4.02(m,0.5H), 3.65–3.55(m,0.5H),3.19–3.08(m,1H),2.93–2.86(m,0.5H),2.23–2.13(m,1H),2.11–2.02 (m,1H),1.94–1.83(m,1H),1.60–1.49(m,1H).
Embodiment 32
(R) -1- (3- (4- amino -3- (3- (3,4- difluoros phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] Pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of bis- fluoro- 4- of compound 1,2- (propyl- 2- alkynes -1- bases epoxide) benzene
3,4- difluorophenols (1g, 7.687mmol) are dissolved in acetone (35mL), then add Anhydrous potassium carbonate (3.2g, 23.06mmol) and 3- propargyl bromides (1mL, 9.22mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, add Hot back flow reaction 24 hours.After reaction completely, filtering, concentration filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v)= 80/1) weak yellow liquid 1.22g, yield, are obtained：94.4%.LC-MS:(pos.ion)m/z:169.04[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (3,4- difluoros phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.3014mmol) is dissolved in DMF (15mL), continuously adds 1,2-, bis- fluoro- 4- (propyl- 2- alkynes -1- bases epoxide) benzene (105mg, 0.6027mmol), cuprous iodide (12mg, 0.0602mmol), triethylamine (18mg, 0.1808mmol) and four (triphens Base phosphine) palladium (18mg, 0.0150mmol).Under nitrogen protections, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentrated solvent, Add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v) =35/1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=20/1), obtains oily yellow solid 37mg, yield：28.01%.
LC-MS:(pos.ion)m/z:439.16[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.25(s,1H),7.41(dd,J1=19.2Hz, J2=9.5Hz, 1H), 7.32-7.24 (m, 1H), 6.95 (d, J=8.3Hz, 1H), 6.86-6.67 (m, 1H), 6.16-6.01 (m, 1H), 5.74- 5.56(m,1H),5.18(s,2H),4.74–4.58(m,1H),4.54–4.46(m,0.5H),4.33–4.14(m,1H),4.11– 4.01(m,0.5H),3.65–3.56(m,0.5H),3.19–3.07(m,1H),2.97–2.85(m,0.5H),2.22–2.13(m, 1H),2.11–2.01(m,1H),1.93–1.83(m,1H),1.61–1.50(m,1H).
Embodiment 33
(R) -1- (3- (4- amino -3- (3- (the chloro- 3- fluorophenoxies of 2-) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] Pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of the fluoro- 3- of the chloro- 1- of compound 2- (propyl- 2- alkynes -1- bases epoxide) benzene
The chloro- 3- fluorophenols (1g, 6.8236mmol) of 2- are dissolved in acetone (35mL), then add Anhydrous potassium carbonate (2.8g, 20.47mmol) and 3- propargyl bromides (1mL, 8.188mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, add Hot back flow reaction 24 hours.After reaction completely, filtering, concentration filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v)= 80/1) weak yellow liquid 1.08g, yield, are obtained：85.7%.LC-MS:(pos.ion)m/z:185.01[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (the chloro- 3- fluorophenoxies of 2-) propyl- 1- alkynes -1- bases) -1H- Pyrazolo [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.3014mmol) is dissolved in DMF (15mL), continuously adds the fluoro- 3- of the chloro- 1- of 2- (propyl- 2- alkynes -1- bases epoxide) benzene (115mg, 0.6027mmol), cuprous iodide (12mg, 0.0602mmol), triethylamine (18mg, 0.1808mmol) and four (triphens Base phosphine) palladium (18mg, 0.0150mmol).Under nitrogen protections, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentrated solvent, Add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v) =32/1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=18/1), obtains oily yellow solid 33mg, yield：24.07%.
LC-MS:(pos.ion)m/z:455.13[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.25 (s, 1H), 7.41 (d, J=6.9Hz, 1H), 7.28 (d, J= 7.9Hz, 1H), 7.08 (t, J=8.2Hz, 1H), 6.86-6.68 (m, 1H), 6.17-6.02 (m, 1H), 5.74-5.56 (m, 1H),5.33(s,2H),4.73–4.58(m,1H),4.54–4.47(m,0.5H),4.32–4.13(m,1H),4.10–4.02(m, 0.5H),3.64–3.55(m,0.5H),3.19–3.07(m,1H),2.94–2.85(m,0.5H),2.23–2.13(m,1H), 2.11–2.02(m,1H),1.94–1.82(m,1H),1.61–1.49(m,1H).
Embodiment 34
(R) -1- (3- (4- amino -3- (3- (the chloro- 2- fluorophenoxies of 3-) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] Pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of the fluoro- 3- of the chloro- 2- of compound 1- (propyl- 2- alkynes -1- bases epoxide) benzene
The chloro- 2- fluorophenols (1g, 6.8236mmol) of 3- are dissolved in acetone (35mL), then add Anhydrous potassium carbonate (2.8g, 20.47mmol) and 3- propargyl bromides (1mL, 8.188mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, add Hot back flow reaction 24 hours.After reaction completely, filtering, concentration filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v)= 80/1) weak yellow liquid 1.21g, yield, are obtained：96.1%.LC-MS:(pos.ion)m/z:185.01[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (the chloro- 2- fluorophenoxies of 3-) propyl- 1- alkynes -1- bases) -1H- Pyrazolo [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.3014mmol) is dissolved in DMF (15mL), continuously adds the fluoro- 3- of the chloro- 2- of 1- (propyl- 2- alkynes -1- bases epoxide) benzene (115mg, 0.6027mmol), cuprous iodide (12mg, 0.0602mmol), triethylamine (18mg, 0.1808mmol) and four (triphens Base phosphine) palladium (18mg, 0.0150mmol).Under nitrogen protections, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentrated solvent, Add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v) =32/1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=18/1), obtains oily yellow solid 38mg, yield：27.7%.
LC-MS:(pos.ion)m/z:455.13[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.29 (s, 1H), 7.52-7.38 (m, 1H), 7.22 (d, J= 7.4Hz,2H),6.87–6.66(m,1H),6.21–6.03(m,1H),5.74–5.55(m,1H),5.30(s,2H),4.79– 4.59(m,1H),4.55–4.45(m,0.5H),4.35–4.14(m,1H),4.11–4.02(m,0.5H),3.65–3.55(m, 0.5H),3.20–3.05(m,1H),2.95–2.85(m,0.5H),2.27–2.12(m,1H),2.12–2.01(m,1H),1.96– 1.81(m,1H),1.63–1.49(m,1H).
Embodiment 35
(R) -1- (3- (4- amino -3- (3- (the chloro- 3- fluorophenoxies of 4-) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] Pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of the fluoro- 4- of the chloro- 2- of compound 1- (propyl- 2- alkynes -1- bases epoxide) benzene
The chloro- 3- fluorophenols (800mg, 5.458mmol) of 4- are dissolved in acetone (35mL), then add Anhydrous potassium carbonate (2.3g, 16.37mmol) and 3- propargyl bromides (0.6mL, 6.55mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, Heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v) are concentrated =60/1) weak yellow liquid 910mg, yield, are obtained：90.3%.
LC-MS:(pos.ion)m/z:185.01[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (the chloro- 3- fluorophenoxies of 4-) propyl- 1- alkynes -1- bases) -1H- Pyrazolo [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.3014mmol) is dissolved in DMF (15mL), continuously adds the fluoro- 4- of the chloro- 2- of 1- (propyl- 2- alkynes -1- bases epoxide) benzene (115mg, 0.6027mmol), cuprous iodide (12mg, 0.0602mmol), triethylamine (18mg, 0.1808mmol) and four (triphens Base phosphine) palladium (18mg, 0.0150mmol).Under nitrogen protections, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentrated solvent, Add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v) =35/1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=20/1), obtains oily yellow solid 32mg, yield：26.2%.
LC-MS:(pos.ion)m/z:455.13[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.24 (s, 1H), 7.54 (t, J=8.8Hz, 1H), 7.28 (dd, J1 =11.3Hz, J2=2.6Hz, 1H), 7.00 (dd, J1=8.8Hz, J2=1.8Hz, 1H), 6.85-6.67 (m, 1H), 6.15- 6.02(m,1H),5.73–5.55(m,1H),5.21(s,2H),4.73–4.59(m,1H),4.54–4.47(m,0.5H),4.33– 4.14(m,1H),4.10–4.01(m,0.5H),3.63–3.57(m,0.5H),3.18–3.07(m,1H),2.97–2.88(m, 0.5H),2.22–2.12(m,1H),2.11–2.02(m,1H),1.93–1.83(m,1H),1.61–1.49(m,1H).
Embodiment 36
(R) -1- (3- (4- amino -3- (3- (the chloro- 2- fluorophenoxies of 5-) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] Pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of the fluoro- 2- of compound 4-chloro -1- (propyl- 2- alkynes -1- bases epoxide) benzene
The chloro- 2- fluorophenols (800mg, 5.458mmol) of 5- are dissolved in acetone (35mL), then add Anhydrous potassium carbonate (2.3g, 16.37mmol) and 3- propargyl bromides (0.6mL, 6.55mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, Heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v) are concentrated =80/1) weak yellow liquid 900mg, yield, are obtained：89.3%.
LC-MS:(pos.ion)m/z:185.01[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (the chloro- 2- fluorophenoxies of 5-) propyl- 1- alkynes -1- bases) -1H- Pyrazolo [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.3014mmol) is dissolved in DMF (15mL), continuously adds the fluoro- 2- of the chloro- 1- of 4- (propyl- 2- alkynes -1- bases epoxide) benzene (115mg, 0.6027mmol), cuprous iodide (12mg, 0.0602mmol), triethylamine (18mg, 0.1808mmol) and four (triphens Base phosphine) palladium (18mg, 0.0150mmol).Under nitrogen protections, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentrated solvent, Add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v) =35/1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=20/1), obtains oily yellow solid 33mg, yield：24.07%.
LC-MS:(pos.ion)m/z:455.13[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.25 (s, 1H), 7.50 (d, J=9.9Hz, 1H), 7.48-7.40 (m, 1H), 7.29 (d, J=6.5Hz, 1H), 6.88-6.67 (m, 1H), 6.19-6.00 (m, 1H), 5.73-5.55 (m, 1H), 5.27(s,2H),4.79–4.57(m,1H),4.55–4.45(m,0.5H),4.36–4.13(m,1H),4.10–4.02(m, 0.5H),3.66–3.55(m,0.5H),3.19–3.06(m,1H),2.97–2.85(m,0.5H),2.24–2.12(m,1H), 2.10–2.01(m,1H),1.96–1.81(m,1H),1.63–1.47(m,1H).
Embodiment 37
(R) -1- (3- (4- amino -3- (3- (3- (pyridin-4-yl methoxyl group) phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 4- ((3- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) methyl) pyridine
3- (propyl- 2- alkynes -1- bases epoxide) phenol (400mg, 2.699mmol) is dissolved in and is dissolved in DMF (20mL), then Anhydrous potassium carbonate (1.6g, 10.799mmol) and 4- bromo methyl cycloheptapyridines (750mg, 2.969mmol) are added, reacts at room temperature 16h.Stop Only react, concentrated solvent, into reaction solution plus water (100mL), dichloromethane take (50mL × 3).Merge organic phase, anhydrous slufuric acid Sodium is dried, and concentration, silica gel column chromatography separating purification (DCM/MeOH (v/v)=50/1), obtains brown liquid 420mg, yield： 65%.
LC-MS:(pos.ion)m/z:240.09[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (3- (pyridin-4-yl methoxyl group) phenoxy group) propyl- 1- alkynes - 1- yls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.3014mmol) is dissolved in DMF (15mL), continuously adds 4- ((3- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) first Base) pyridine (150mg, 0.6027mmol), cuprous iodide (12mg, 0.0602mmol), triethylamine (18mg, 0.1808mmol) and Tetrakis triphenylphosphine palladium (18mg, 0.0150mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stop reaction, filtering is dense Contracting solvent, add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/ MeOH (v/v)=25/1), crude product is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=15/1), obtains oil yellow Color solid 40mg, yield：26.05%.
LC-MS:(pos.ion)m/z:510.22[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.64–8.48(m,2H),8.25(s,1H),7.54–7.39(m, 2H),7.26(s,1H),6.89–6.78(m,1H),6.78–6.57(m,3H),6.19–6.02(m,1H),5.73–5.56(m, 1H),5.20(s,2H),5.15(s,2H),4.73–4.57(m,1H),4.56–4.48(m,0.5H),4.34–4.14(m,1H), 4.12–4.02(m,0.5H),3.63–3.54(m,0.5H),3.17–3.07(m,1H),2.93–2.85(m,0.5H),2.23– 2.12(m,1H),2.10–2.01(m,1H),1.94–1.81(m,1H),1.63–1.48(m,1H).
Embodiment 38
(R) -1- (3- (4- amino -3- (3- (3- (pyridin-3-yl methoxyl group) phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 3- (pyridin-3-yl methoxyl group) phenol
Resorcinol (1.3g, 12mmol) is dissolved in and is dissolved in DMF (50mL), then add Anhydrous potassium carbonate (2.5g, 18mmol) with 3- bromo methyl cycloheptapyridines hydrobromate (1.5g, 5.9mmol), 12h is reacted at room temperature.Stop reacting, concentrated solvent, to In reaction solution plus water (100mL), ethyl acetate extract (50mL × 3).Merge organic phase, anhydrous sodium sulfate drying, concentration, silica gel Column chromatographic isolation and purification (PE/EtOAc (v/v)=3/1), obtains faint yellow solid 670mg, yield：56%.
LC-MS:(pos.ion)m/z:202.08[M+1]+.
Step 2：The synthesis of compound 3- ((3- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) methyl) pyridine
3- (pyridin-3-yl methoxyl group) phenol (500mg, 2.4848mmol) is dissolved in acetone (30mL), Ran Houjia Enter Anhydrous potassium carbonate (1.1g, 7.454mmol) and 3- propargyl bromides (0.26mL, 2.981mmol, 1.38g/mL).Replace nitrogen three It is secondary, under nitrogen protection, heating reflux reaction 15 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification are concentrated (PE/EtOAc (v/v)=10/1), obtains weak yellow liquid 61mg, yield：10.2%.
LC-MS:(pos.ion)m/z:240.09[M+1]+.
Step 3：Compound (R) -1- (3- (4- amino -3- (3- (3- (pyridin-3-yl methoxyl group) phenoxy group) propyl- 1- alkynes - 1- yls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (95mg, 0.2386mmol) is dissolved in DMF (15mL), continuously adds 3- ((3- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) first Base) pyridine (60mg, 0.2386mmol), cuprous iodide (10mg, 0.047mmol), triethylamine (14mg, 0.143mmol) and four (triphenylphosphine) palladium (14mg, 0.011mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentration Solvent, add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v) crude product=25/1), is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=15/1), obtains oil yellow color and consolidate Body 28mg, yield：23.03%.
LC-MS:(pos.ion)m/z:510.22[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.67(s,1H),8.54(s,1H),8.24(s,1H),7.87(d,J =7.5Hz, 1H), 7.46-7.35 (m, 1H), 7.25 (t, J=8.1Hz, 1H), 6.89-6.80 (m, 1H), 6.78 (s, 1H), 6.72–6.66(m,2H),6.17–6.01(m,1H),5.72–5.55(m,1H),5.16(s,2H),5.15(s,2H),4.75– 4.57(m,1H),4.55–4.46(m,0.5H),4.36–4.12(m,1H),4.09–4.01(m,0.5H),3.63–3.55(m, 0.5H),3.17–3.07(m,1H),2.92–2.84(m,0.5H),2.22–2.11(m,1H),2.11–2.01(m,1H),1.94– 1.82(m,1H),1.60–1.50(m,1H).
Embodiment 39
(R) -1- (3- (4- amino -3- (3- (2- fluorophenoxies) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine - 1- yls) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of the fluoro- 2- of compound 1- (propyl- 2- alkynes -1- bases epoxide) benzene
2- fluorophenols (600mg, 5.352mmol) are dissolved in acetone (30mL), then add Anhydrous potassium carbonate (2.3g, 16.05mmol) and 3- propargyl bromides (0.6mL, 6.4228mmol, 1.38g/mL).Replace nitrogen three times, nitrogen protection Under, heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/ are concentrated V)=60/1), weak yellow liquid 600mg, yield are obtained：74.6%.
LC-MS:(pos.ion)m/z:151.05[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (2- fluorophenoxies) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.3014mmol) is dissolved in DMF (15mL), continuously adds the fluoro- 2- of 1- (propyl- 2- alkynes -1- bases epoxide) benzene (100mg, 0.6027mmol), cuprous iodide (12mg, 0.0602mmol), triethylamine (18mg, 0.1808mmol) and four (triphens Base phosphine) palladium (18mg, 0.0150mmol).Under nitrogen protections, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentrated solvent, Add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v) =35/1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=18/1), obtains oily yellow solid 40mg, yield：31.57%.
LC-MS:(pos.ion)m/z:421.17[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.24 (s, 1H), 7.41 (t, J=8.3Hz, 1H), 7.30-7.23 (m, 1H), 7.19 (t, J=7.8Hz, 1H), 7.01 (dd, J1=11.5Hz, J2=7.5Hz, 1H), 6.85-6.69 (m, 1H), 6.15–6.03(m,1H),5.74–5.56(m,1H),5.25(s,2H),4.75–4.59(m,1H),4.55–4.47(m,0.5H), 4.33–4.14(m,1H),4.09–4.02(m,0.5H),3.64–3.56(m,0.5H),3.20–3.06(m,1H),2.94–2.85 (m,0.5H),2.24–2.13(m,1H),2.12–2.01(m,1H),1.94–1.81(m,1H),1.62–1.48(m,1H).
Embodiment 40
(R) -1- (3- (4- amino -3- (3- (4- fluorophenoxies) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine - 1- yls) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of the fluoro- 4- of compound 1- (propyl- 2- alkynes -1- bases epoxide) benzene
4- fluorophenols (600mg, 5.352mmol) are dissolved in acetone (30mL), then add Anhydrous potassium carbonate (2.3g, 16.05mmol) and 3- propargyl bromides (0.6mL, 6.4228mmol, 1.38g/mL).Replace nitrogen three times, nitrogen protection Under, heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/ are concentrated V)=60/1), weak yellow liquid 400mg, yield are obtained：49.7%.
LC-MS:(pos.ion)m/z:151.05[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (4- fluorophenoxies) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.3014mmol) is dissolved in DMF (15mL), continuously adds the fluoro- 4- of 1- (propyl- 2- alkynes -1- bases epoxide) benzene (100mg, 0.6027mmol), cuprous iodide (12mg, 0.0602mmol), triethylamine (18mg, 0.1808mmol) and four (triphens Base phosphine) palladium (18mg, 0.0150mmol).Under nitrogen protections, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentrated solvent, Add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v) =38/1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=20/1), obtains oily yellow solid 50mg, yield：39.4%.
LC-MS:(pos.ion)m/z:421.17[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.24(s,1H),7.28–7.15(m,2H),7.15–7.06(m, 2H),6.87–6.68(m,1H),6.19–6.00(m,1H),5.73–5.55(m,1H),5.15(s,2H),4.75–4.58(m, 1H),4.55–4.46(m,0.5H),4.33–4.14(m,1H),4.09–4.01(m,0.5H),3.65–3.55(m,0.5H), 3.20–3.07(m,1H),2.95–2.86(m,0.5H),2.22–2.11(m,1H),2.11–2.02(m,1H),1.94–1.81 (m,1H),1.62–1.49(m,1H).
Embodiment 41
(R) ((4- amino -3- (3- (pyridine -2- bases epoxide) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] are phonetic by 3- by -1- Pyridine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 2- (propyl- 2- alkynes -1- bases epoxide) pyridine
2 hydroxy pyrimidine (600mg, 6.309mmol) is dissolved in acetone (30mL), then adds Anhydrous potassium carbonate (2.7g, 18.93mmol) and 3- propargyl bromides (0.7mL, 7.57mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, Heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v) are concentrated =4/1) weak yellow liquid 420mg, yield, are obtained：50%.
LC-MS:(pos.ion)m/z:134.05[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (pyridine -2- bases epoxide) propyl- 1- alkynes -1- bases) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.3014mmol) is dissolved in DMF (15mL), continuously add 2- (propyl- 2- alkynes -1- bases epoxide) pyridine (80mg, 0.6027mmol), cuprous iodide (12mg, 0.0602mmol), triethylamine (18mg, 0.1808mmol) and tetrakis triphenylphosphine palladium (18mg,0.0150mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filtering, concentrated solvent, adds full With saline solution (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=38/ 1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=20/1), obtains faint yellow solid 42mg, produces Rate：34.55%.
LC-MS:(pos.ion)m/z:404.18[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.23 (s, 1H), 7.88 (d, J=6.3Hz, 1H), 7.56-7.47 (m, 1H), 6.87-6.67 (m, 1H), 6.49 (d, J=9.1Hz, 1H), 6.34 (t, J=6.6Hz, 1H), 6.17-6.03 (m, 1H),5.74–5.57(m,1H),5.04(s,2H),4.74–4.58(m,1H),4.54–4.44(m,0.5H),4.32–4.12(m, 1H),4.11–4.01(m,0.5H),3.66–3.52(m,0.5H),3.19–3.05(m,1H),2.95–2.85(m,0.5H), 2.21–2.11(m,1H),2.10–2.01(m,1H),1.93–1.82(m,1H),1.60–1.49(m,1H).
Embodiment 42
(R) ((4- amino -3- (3- (pyridin-3-yl epoxide) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] are phonetic by 3- by -1- Pyridine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 3- (propyl- 2- alkynes -1- bases epoxide) pyridine
3- pyridones (800mg, 8.142mmol) are dissolved in acetone (50mL), then add Anhydrous potassium carbonate (3.5g, 25.24mmol) and 3- propargyl bromides (0.9mL, 10.09mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, Heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v) are concentrated =6/1) yellow liquid 100mg, yield, are obtained：8.9%.
LC-MS:(pos.ion)m/z:134.05[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (pyridin-3-yl epoxide) propyl- 1- alkynes -1- bases) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.3014mmol) is dissolved in DMF (15mL), continuously add 3- (propyl- 2- alkynes -1- bases epoxide) pyridine (80mg, 0.6027mmol), cuprous iodide (12mg, 0.0602mmol), triethylamine (18mg, 0.1808mmol) and tetrakis triphenylphosphine palladium (18mg,0.0150mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filtering, concentrated solvent, adds full With saline solution (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=30/ 1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=16/1), obtains oily yellow solid 33mg, produces Rate：27.15%.
LC-MS:(pos.ion)m/z:404.18[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.44 (s, 1H), 8.34-8.20 (m, 2H), 7.58 (d, J= 7.2Hz,1H),7.40(dd,J1=8.1Hz, J2=4.5Hz, 1H), 6.86-6.67 (m, 1H), 6.19-6.01 (m, 1H), 5.74–5.55(m,1H),5.26(s,2H),4.73–4.57(m,1H),4.54–4.45(m,0.5H),4.34–4.13(m,1H), 4.11–4.01(m,0.5H),3.63–3.56(m,0.5H),3.20–3.06(m,1H),2.95–2.84(m,0.5H),2.23– 2.11(m,1H),2.10–2.01(m,1H),1.93–1.82(m,1H),1.61–1.49(m,1H).
Embodiment 43
(R) -3- ((3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl-s 2- alkynes -1- bases) epoxide) benzonitrile
Step 1：The synthesis of compound 3- (propyl- 2- alkynes -1- bases epoxide) benzonitrile
3- 4-hydroxy-benzonitriles (800mg, 6.7159mmol) are dissolved in acetone (35mL), then add Anhydrous potassium carbonate (2.8g, 20.148mmol) and 3- propargyl bromides (0.7mL, 8.059mmol, 1.38g/mL).Replace nitrogen three times, nitrogen protection Under, heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/ are concentrated V)=15/1), white solid 800mg, yield are obtained：75.7%.
LC-MS:(pos.ion)m/z:158.05[M+1]+.
Step 2：Compound (R) -3- ((3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] Pyrimidin-3-yl) propyl- 2- alkynes -1- bases) epoxide) and benzonitrile synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.3014mmol) is dissolved in DMF (15mL), continuously add 3- (propyl- 2- alkynes -1- bases epoxide) benzonitrile (95mg, 0.6027mmol), cuprous iodide (12mg, 0.0602mmol), triethylamine (18mg, 0.1808mmol) and tetrakis triphenylphosphine palladium (18mg,0.0150mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filtering, concentrated solvent, adds full With saline solution (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=35/ 1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=18/1), obtains faint yellow solid 40mg, produces Rate：31.05%.
LC-MS:(pos.ion)m/z:428.18[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.24 (s, 1H), 7.62 (s, 1H), 7.56 (t, J=7.9Hz, 1H),7.52–7.43(m,2H),6.86–6.66(m,1H),6.18–6.01(m,1H),5.73–5.54(m,1H),5.25(s, 2H),4.73–4.57(m,1H),4.55–4.45(m,0.5H),4.34–4.13(m,1H),4.10–4.00(m,0.5H),3.65– 3.54(m,0.5H),3.19–3.06(m,1H),2.95–2.86(m,0.5H),2.22–2.12(m,1H),2.10–2.02(m, 1H),1.94–1.81(m,1H),1.63–1.49(m,1H).
Embodiment 44
(R) -1- (3- (4- amino -3- (3- ((the chloro- 4- fluorophenyls of 3-) amino) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3, 4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of the fluoro- N- of compound 3-chlorin -4- (propyl- 2- alkynes -1- bases) aniline
The chloro- 4- fluoroanilines (1.2g, 8.2mmol) of 3- are dissolved in ethanol (40mL), then add natrium carbonicum calcinatum (1.1g, 9.9mmol) and 3- propargyl bromides (0.9mL, 9.9mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, heating Back flow reaction 15 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v)=70/ are concentrated 1) white solid 350mg, yield, are obtained：23%.LC-MS:(pos.ion)m/z:184.03[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- ((the chloro- 4- fluorophenyls of 3-) amino) propyl- 1- alkynes -1- bases) - 1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.3014mmol) is dissolved in DMF (15mL), continuously adds the fluoro- N- of the chloro- 4- of 3- (propyl- 2- alkynes -1- bases) aniline (110mg, 0.6027mmol), cuprous iodide (12mg, 0.0602mmol), triethylamine (18mg, 0.1808mmol) and four (triphens Base phosphine) palladium (18mg, 0.0150mmol).Under nitrogen protections, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentrated solvent, Add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v) =35/1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=18/1), obtains brown solid 49mg, yield：35.82%.
LC-MS:(pos.ion)m/z:454.15[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.22(s,1H),7.18(s,1H),6.96–6.86(m,1H), 6.86–6.76(m,1H),6.75–6.67(m,1H),6.35(s,1H),6.18–5.99(m,1H),5.73–5.53(m,1H), 4.76–4.56(m,1H),4.54–4.45(m,0.5H),4.26(s,2H),4.22–4.11(m,1H),4.08–4.02(m, 0.5H),3.62–3.55(m,0.5H),3.16–3.07(m,1H),2.95–2.84(m,0.5H),2.20–2.10(m,1H), 2.10–2.00(m,1H),1.93–1.82(m,1H),1.60–1.48(m,1H).
Embodiment 45
(R) -1- (3- (4- amino -3- (3- (3- phenoxy-phenoxies) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] Pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 1- phenoxy groups -3- (propyl- 2- alkynes -1- bases epoxide) benzene
3- phenoxy phenyls (800mg, 4.2962mmol) are dissolved in acetone (30mL), then add Anhydrous potassium carbonate (1.8g, 12.88mmol) and 3- propargyl bromides (0.56mL, 6.44mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, Heating reflux reaction 24 hours.After reaction completely, filtering, concentration filtrate, addition water (80mL), dichloromethane extraction (50mL × 3), merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filter, concentration, obtain pale yellow oil 0.9g, produce Rate：90%.
LC-MS:(pos.ion)m/z:225.08[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (3- phenoxy-phenoxies) propyl- 1- alkynes -1- bases) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (140mg, 0.3516mmol) is dissolved in DMF (15mL), continuously adds 1- phenoxy groups -3- (propyl- 2- alkynes -1- bases epoxide) benzene (120mg, 0.5274mmol), cuprous iodide (14mg, 0.0703mmol), triethylamine (21mg, 0.2109mmol) and four (triphens Base phosphine) palladium (21mg, 0.0175mmol).Under nitrogen protections, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentrated solvent, Add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v) =30/1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=16/1), obtains faint yellow solid 50mg, yield：28.7%.
LC-MS:(pos.ion)m/z:495.21[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.25(s,1H),7.41–7.29(m,3H),7.16–7.09(m, 1H), 7.04 (d, J=7.6Hz, 2H), 6.89 (d, J=7.7Hz, 1H), 6.75 (s, 1H), 6.73-6.65 (m, 1H), 6.61 (d, J=7.5Hz, 1H), 6.14-6.06 (m, 1H), 5.72-5.59 (m, 1H), 5.15 (s, 2H), 4.69-4.59 (m, 1H), 4.56–4.47(m,0.5H),4.34–4.13(m,1H),4.11–3.98(m,0.5H),3.64–3.55(m,0.5H),3.17– 3.09(m,1H),2.93–2.86(m,0.5H),2.23–2.12(m,1H),2.12–2.03(m,1H),1.93–1.82(m,1H), 1.63–1.51(m,1H).
Embodiment 46
(R) -1- (3- (4- amino -3- (3- (3- (thiazol-2-yl methoxyl group) phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound thiazol-2-yl methanol
2- aldehyde radicals thiazole (2g, 17.677mmol) is dissolved in methanol (50mL), 0 DEG C add sodium borohydride (1.2g, 30.051mmol), continue to react 15min, react 4h at room temperature.After reaction completely, ammonium chloride saturated solution (120mL) is added, Ethyl acetate extracts (60mL × 3), merges organic phase, anhydrous sodium sulfate drying；Filtering, concentration, obtains white solid 1.6g, produces Rate：91.7%.
LC-MS:(pos.ion)m/z:116.01[M+1]+.
Step 2：The synthesis of compound 2- ((3- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) methyl) thiazole
By 3- (propyl- 2- alkynes -1- bases epoxide) phenol (650mg, 4.387mmol) and thiazol-2-yl methanol (560mg, 4.825mmol) be dissolved in THF (20mL), then sequentially add triphenylphosphine (1.6g, 6.142mmol) and DIAD (1.3mL, 6.142mmol, 1.02g/mL), under nitrogen protection, reaction 15h is stirred at room temperature.After reaction completely, saturated aqueous common salt is added (100mL), ethyl acetate extraction (50mL × 3), merge organic phase, anhydrous sodium sulfate drying, concentrated solvent.Silica gel column chromatography point From purifying (PE/EtOAc (v/v)=8/1), light yellow viscous liquid 230mg, yield are obtained：21.3%.
LC-MS(pos.ion)m/z:246.05[M+1]+.
Step 3：Compound (R) -1- (3- (4- amino -3- (3- (3- (thiazol-2-yl methoxyl group) phenoxy group) propyl- 1- alkynes - 1- yls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (170mg, 0.426mmol) is dissolved in DMF (15mL), continuously adds 2- ((3- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) first Base) thiazole (210mg, 0.853mmol), cuprous iodide (17mg, 0.0853mmol), triethylamine (26mg, 0.256mmol) and four (triphenylphosphine) palladium (25mg, 0.0213mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentration Solvent, add saturated aqueous common salt (100mL), dichloromethane extraction (50mL × 3).Silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v) faint yellow solid 48mg, yield=15/1), are obtained：21.8%.
LC-MS:(pos.ion)m/z:516.17[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.24 (s, 1H), 7.80 (d, J=47.0Hz, 2H), 7.27 (s, 1H),6.91–6.62(m,4H),6.27–5.99(m,1H),5.78–5.57(m,1H),5.45(s,2H),5.16(s,2H), 4.79–4.58(m,1H),4.57–4.43(m,0.5H),4.36–4.15(m,1H),4.08–4.00(m,0.5H),3.65–3.56 (m,0.5H),3.19–3.14(m,1H),2.96–2.82(m,0.5H),2.25–2.11(m,1H),2.13–1.99(m,1H), 1.95–1.77(m,1H),1.66–1.49(m,1H).
Embodiment 47
(R) -1- (3- (4- amino -3- (3- (3- (thiazole -5- ylmethoxies) phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 5- ((3- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) methyl) thiazole
By 3- (propyl- 2- alkynes -1- bases epoxide) phenol (1g, 6.749mmol) and 5-Hydroxymethylthiazole (900mg, 7.424mmol) be dissolved in THF (25mL), then sequentially add triphenylphosphine (2.5g, 9.449mmol) and DIAD (1.9mL, 9.449mmol, 1.02g/mL), under nitrogen protection, reaction 15h is stirred at room temperature.After reaction completely, saturated aqueous common salt is added (100mL), ethyl acetate extraction (50mL × 3), merge organic phase, anhydrous sodium sulfate drying, concentrated solvent.Silica gel column chromatography point From purifying (PE/EtOAc (v/v)=8/1), white solid 1.45g, yield are obtained：87.6%.
LC-MS(pos.ion)m/z:246.05[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (3- (thiazole -5- ylmethoxies) phenoxy group) propyl- 1- alkynes - 1- yls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (150mg, 0.3767mmol) is dissolved in DMF (15mL), continuously adds 5- ((3- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) first Base) thiazole (169mg, 0.652mmol), cuprous iodide (15mg, 0.0753mmol), triethylamine (23mg, 0.226mmol) and four (triphenylphosphine) palladium (22mg, 0.0188mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentration Solvent, add saturated aqueous common salt (100mL), dichloromethane extraction (50mL × 3).Silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v) faint yellow solid 18mg, yield=18/1), are obtained：9.2%.
LC-MS:(pos.ion)m/z:516.17[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)9.11(s,1H),8.24(s,1H),8.01(s,1H),7.25(t,J =8.1Hz, 1H), 6.89-6.80 (m, 1H), 6.77 (s, 1H), 6.72 (d, J=7.5Hz, 1H), 6.68 (d, J=7.9Hz, 1H),6.15–6.03(m,1H),5.72–5.58(m,1H),5.40(s,2H),5.15(s,2H),4.69–4.57(m,1H), 4.54–4.46(m,0.5H),4.29–4.14(m,1H),4.09–4.03(m,0.5H),3.64–3.55(m,0.5H),3.18– 3.06(m,1H),2.92–2.87(m,0.5H),2.21–2.12(m,1H),2.11–2.03(m,1H),1.93–1.84(m,1H), 1.61–1.51(m,1H).
Embodiment 48
(R) -1- (3- (4- amino -3- (3- ((the chloro- 3- fluorophenyls of 4-) amino) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3, 4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of the fluoro- N- of compound 4-chloro -3- (propyl- 2- alkynes -1- bases) aniline
The fluoro- 4- chloroanilines (1.3g, 8.9mmol) of 3- are dissolved in ethanol (40mL), then add natrium carbonicum calcinatum (1.1g, 11mmol) and 3- propargyl bromides (0.77mL, 8.9mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, heating Back flow reaction 15 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v)=70/ are concentrated 1) white solid 400mg, yield, are obtained：21%.LC-MS:(pos.ion)m/z:184.03[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- ((the chloro- 3- fluorophenyls of 4-) amino) propyl- 1- alkynes -1- bases) - 1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.3014mmol) is dissolved in DMF (15mL), continuously adds the fluoro- N- of the chloro- 3- of 4- (propyl- 2- alkynes -1- bases) aniline (110mg, 0.6027mmol), cuprous iodide (12mg, 0.0602mmol), triethylamine (18mg, 0.1808mmol) and four (triphens Base phosphine) palladium (18mg, 0.0150mmol).Under nitrogen protections, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentrated solvent, Add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v) =35/1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=18/1), obtains beige solid 60mg, yield：43.8%.
LC-MS:(pos.ion)m/z:454.15[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.23 (s, 1H), 7.27 (t, J=8.3Hz, 1H), 6.89-6.79 (m, 1H), 6.75 (d, J=11.9Hz, 1H), 6.66 (s, 1H), 6.59 (d, J=7.9Hz, 1H), 6.16-6.02 (m, 1H), 5.73-5.55 (m, 1H), 4.69-4.57 (m, 1H), 4.55-4.45 (m, 0.5H), 4.27 (d, J=4.9Hz, 2H), 4.23- 4.11(m,1H),4.09–4.02(m,0.5H),3.63–3.53(m,0.5H),3.17–3.06(m,1H),2.94–2.85(m, 0.5H),2.20–2.11(m,1H),2.09–2.00(m,1H),1.91–1.83(m,1H),1.61–1.48(m,1H).
Embodiment 49
(R) -1- (3- (4- amino -3- (3- (3- (thiazol-2-yl epoxide) phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrazoles And [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 2- (3- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) thiazole
3- (propyl- 2- alkynes -1- bases epoxide) phenol (500mg, 3.374mmol) is dissolved in and is dissolved in DMF (20mL), then Anhydrous potassium carbonate (700mg, 5.061mmol) is added, is heated to 130 DEG C, reacts 45min.By 2- bromo thiazoles (0.4mL, 4.049mmol) it is slowly dropped in above-mentioned solution, reacts 24h at 130 DEG C.Stop reaction, concentrated solvent, add into reaction solution Water (100mL), dichloromethane extraction (50mL × 3).Merge organic phase, anhydrous sodium sulfate drying, concentration, silica gel column chromatography separation Purify (PE/EtOAc (v/v)=40/1), obtain weak yellow liquid 300mg, yield：38.4%.
LC-MS:(pos.ion)m/z:232.04[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (3- (thiazol-2-yl epoxide) phenoxy group) propyl- 1- alkynes -1- Base) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (170mg, 0.4269mmol) is dissolved in DMF (15mL), continuously adds 2- (3- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) thiophene Azoles (200mg, 0.8538mmol), cuprous iodide (17mg, 0.0853mmol), triethylamine (26mg, 0.2562mmol) and four (three Phenylphosphine) palladium (25mg, 0.0213mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentration is molten Agent, add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/ V)=35/1), crude product is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=18/1), obtains faint yellow solid 83mg, yield：38.7%.
LC-MS:(pos.ion)m/z:502.16[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.24 (s, 1H), 7.43 (t, J=8.2Hz, 1H), 7.28 (d, J= 3.6Hz, 1H), 7.20 (d, J=2.7Hz, 1H), 7.12 (s, 1H), 7.06 (d, J=8.2Hz, 1H), 7.00-6.93 (m, 1H), 6.84–6.70(m,1H),6.16–6.03(m,1H),5.73–5.57(m,1H),5.20(s,2H),4.69–4.59(m,1H), 4.54–4.47(m,0.5H),4.34–4.14(m,1H),4.09–4.02(m,0.5H),3.59–3.56(m,0.5H),3.19– 3.07(m,1H),2.94–2.84(m,0.5H),2.24–2.13(m,1H),2.10–2.03(m,1H),1.92–1.83(m,1H), 1.62–1.50(m,1H).
Embodiment 50
(R) -1- (3- (4- amino -3- (3- (the fluoro- 5- of 2- (pyridin-3-yl methoxyl group) phenoxy group) propyl- 1- alkynes -1- bases) - 1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 3- ((the fluoro- 3- of 4- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) methyl) pyridine
The fluoro- 3- of 4- (propyl- 2- alkynes -1- bases epoxide) phenol (500mg, 3.009mmol) is dissolved in and is dissolved in DMF (30mL) In, Anhydrous potassium carbonate (1.7g, 12.037mmol) and 3- (bromomethyl) pyridine hydrobromide salt (1g, 3.912mmol) are then added, React at room temperature 15h.Stop reaction, concentrated solvent, into reaction solution plus water (100mL), ethyl acetate extract (50mL × 3).Close And organic phase, anhydrous sodium sulfate drying, concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=5/1), obtain yellowish Color oily liquids 257mg, yield：33.1%.
LC-MS:(pos.ion)m/z:258.09[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (the fluoro- 5- of 2- (pyridin-3-yl methoxyl group) phenoxy group) propyl-s 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (200mg, 0.502mmol) is dissolved in DMF (15mL), continuously adds 3- ((the fluoro- 3- of 4- (propyl- 2- alkynes -1- bases epoxide) benzene oxygen Base) methyl) pyridine (200mg, 0.7534mmol), cuprous iodide (19mg, 0.1005mmol), triethylamine (30mg, 0.301mmol) and tetrakis triphenylphosphine palladium (29mg, 0.0251mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, are stopped Reaction, filtering, concentrated solvent, add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel thin-layer analysis separation Purify (DCM/MeOH (v/v)=15/1), obtain faint yellow solid 48mg, yield：18.11%.
LC-MS:(pos.ion)m/z:528.21[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.68(s,1H),8.53(s,1H),8.24(s,1H),7.87(d,J =7.8Hz, 1H), 7.40 (d, J=5.1Hz, 1H), 7.19 (dd, J1=11.0Hz, J2=9.0Hz, 1H), 7.11 (dd, J1= 7.0Hz,J2=2.6Hz, 1H), 6.89-6.67 (m, 1H), 6.65 (dt, J=8.7,2.9Hz, 1H), 6.15-6.01 (m, 1H), 5.74–5.56(m,1H),5.25(s,2H),5.15(s,2H),4.73–4.57(m,1H),4.55–4.47(m,0.5H),4.32– 4.14(m,1H),4.09–4.00(m,0.5H),3.62–3.53(m,0.5H),3.10–3.06(m,1H),2.89–2.82(m, 0.5H),2.21–2.11(m,1H),2.10–2.02(m,1H),1.93–1.81(m,1H),1.60–1.49(m,1H).
Embodiment 51
(R) -1- (3- (4- amino -3- (3- (the fluoro- 5- of 2- ((3- luorobenzyls) epoxide) phenoxy group) propyl- 1- alkynes -1- bases) - 1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of the fluoro- 3- of compound 4- (propyl- 2- alkynes -1- bases epoxide) phenol
4- fluorine resorcinol (1.62g, 12.60mmol) is dissolved in acetone (50mL), then adds Anhydrous potassium carbonate (3.52g, 25.21mmol) and 3- propargyl bromides (0.87mL, 8.40mmol, 1.38g/mL).Replace nitrogen three times, nitrogen protection Under, heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/ are concentrated V)=20/1), weak yellow liquid 850mg, yield are obtained：51%.
LC-MS:(pos.ion)m/z:167.04[M+1]+.
Step 2：The synthesis of the fluoro- 4- of compound 1- ((3- luorobenzyls) epoxide) -2- (propyl- 2- alkynes -1- bases epoxide) benzene
The fluoro- 3- of 4- (propyl- 2- alkynes -1- bases epoxide) phenol (500mg, 3.009mmol) is dissolved in and is dissolved in DMF (30mL) In, Anhydrous potassium carbonate (1.3g, 9.028mmol) and 3- fluorine bromobenzyl (0.45mL, 3.611mmol, 1.541g/mL) are then added, React at room temperature 16h.Stop reaction, concentrated solvent, into reaction solution plus water (100mL), ethyl acetate extract (50mL × 3).Close And organic phase, anhydrous sodium sulfate drying, concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=40/1), obtain colourless Oily liquids 763mg, yield：92.4%.
LC-MS:(pos.ion)m/z:275.08[M+1]+.
Step 3：Compound (R) -1- (3- (4- amino -3- (3- (the fluoro- 5- of 2- ((3- luorobenzyls) epoxide) phenoxy group) propyl-s 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (130mg, 0.326mmol) is dissolved in DMF (15mL), continuously adds the fluoro- 4- of 1- ((3- luorobenzyls) epoxide) -2- (propyl- 2- Alkynes -1- bases epoxide) benzene (134mg, 0.4897mmol), cuprous iodide (13mg, 0.065mmol), triethylamine (20mg, 0.195mmol) and tetrakis triphenylphosphine palladium (19mg, 0.016mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, are stopped Reaction, filtering, concentrated solvent, add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separates Purify (DCM/MeOH (v/v)=40/1), obtain crude product, then isolate and purify through silica gel thin-layer analysis (DCM/MeOH (v/v)= 18/1) oily yellow solid 71mg, yield, are obtained：39.9%.
LC-MS:(pos.ion)m/z:545.20[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.25 (s, 1H), 7.39 (d, J=5.8Hz, 1H), 7.28 (t, J= 9.2Hz,2H),7.22–7.15(m,1H),7.16–7.07(m,2H),6.84–6.67(m,1H),6.64–6.59(m,1H), 6.17–6.01(m,1H),5.72–5.55(m,1H),5.31–5.06(m,4H),4.77–4.57(m,1H),4.56–4.46(m, 0.5H),4.35–4.14(m,1H),4.09–4.02(m,0.5H),3.62–3.55(m,0.5H),3.18–3.04(m,1H), 2.89–2.82(m,0.5H),2.24–2.11(m,1H),2.10–2.02(m,1H),1.93–1.80(m,1H),1.61–1.48 (m,1H).
Embodiment 52
(R) -1- (3- (4- amino -3- (3- (3- ((5- methylthiazol -2- bases) methoxyl group) phenoxy group) propyl- 1- alkynes -1- Base) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 3- (propyl- 2- alkynes -1- bases epoxide) phenol
Resorcinol (5.5g, 50.437mmol) is dissolved in acetone (100mL), then adds Anhydrous potassium carbonate (11g, 75.656mmol) and 3- propargyl bromides (2.2mL, 25.219mmol, 1.38g/mL).Replace nitrogen three times, nitrogen protection Under, heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/ are concentrated V)=12/1), weak yellow liquid 2.52g, yield are obtained：67%.
LC-MS:(pos.ion)m/z:149.05[M+1]+.
Step 2：The synthesis of compound 5- methyl -2- ((3- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) methyl) thiazole
By 3- (propyl- 2- alkynes -1- bases epoxide) phenol (600mg, 4.049mmol) and 5- methyl -2- thiazoles methanol (627mg, 4.859mmol) it is dissolved in THF (25mL), then sequentially adds triphenylphosphine (1.5g, 5.669mmol), DIAD (1.12mL, 5.669mmol, 1.02g/mL), under nitrogen protection, reaction 15h is stirred at room temperature.After reaction completely, saturated aqueous common salt is added (100mL), ethyl acetate extraction (50mL × 3), merge organic phase, anhydrous sodium sulfate drying, concentrated solvent.Silica gel column chromatography point From purifying (PE/EtOAc (v/v)=10/1), weak yellow liquid 691mg, yield are obtained：65.8%.
LC-MS:(pos.ion)m/z:260.07[M+1]+.
Step 3：Compound (R) -1- (3- (4- amino -3- (3- (3- ((5- methylthiazol -2- bases) methoxyl group) phenoxy group) Propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (140mg, 0.3516mmol) is dissolved in DMF (15mL), continuously adds 5- methyl -2- ((3- (propyl- 2- alkynes -1- bases epoxide) benzene Epoxide) methyl) thiazole (180mg, 0.7032mmol), cuprous iodide (14mg, 0.0703mmol), triethylamine (21mg, 0.2109mmol) and tetrakis triphenylphosphine palladium (21mg, 0.01758mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, are stopped Only react, filter, concentrated solvent, add saturated aqueous common salt (100mL), dichloromethane extraction (50mL × 3).Silica gel thin-layer analysis point From purifying (DCM/MeOH (v/v)=15/1), faint yellow solid 69mg, yield are obtained：37.06%.LC-MS:(pos.ion)m/ z:530.19[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.24 (s, 1H), 7.48 (s, 1H), 7.25 (t, J=8.1Hz, 1H), 6.88-6.81 (m, 1H), 6.78 (s, 1H), 6.73 (d, J=8.0Hz, 1H), 6.69 (d, J=7.7Hz, 1H), 6.17- 6.02(m,1H),5.73–5.56(m,1H),5.35(s,2H),5.15(s,2H),4.70–4.58(m,1H),4.57–4.47(m, 0.5H),4.32–4.15(m,1H),4.10–4.01(m,0.5H),3.64–3.54(m,0.5H),3.17–3.05(m,1H), 2.93–2.83(m,0.5H),2.41(s,3H),2.21–2.12(m,1H),2.11–2.02(m,1H),1.93–1.83(m,1H), 1.62–1.50(m,1H).
Embodiment 53
(R) -1- (3- (4- amino -3- (3- (the fluoro- 5- of 2- (thiazole -5- ylmethoxies) phenoxy group) propyl- 1- alkynes -1- bases) - 1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of the fluoro- 3- of compound 4- (propyl- 2- alkynes -1- bases epoxide) phenol
4- fluorine resorcinol (1.62g, 12.60mmol) is dissolved in acetone (50mL), then adds Anhydrous potassium carbonate (3.52g, 25.21mmol) and 3- propargyl bromides (0.87mL, 8.40mmol, 1.38g/mL).Replace nitrogen three times, nitrogen protection Under, heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/ are concentrated V)=20/1), weak yellow liquid 850mg, yield are obtained：51%.
LC-MS:(pos.ion)m/z:167.04[M+1]+.
Step 2：The synthesis of compound 5- ((the fluoro- 3- of 4- (propyl- 2- alkynes -1- bases epoxide) phenoxy group) methyl) thiazole
By the fluoro- 3- of 4- (propyl- 2- alkynes -1- bases epoxide) phenol (500mg, 3.009mmol) and 5-Hydroxymethylthiazole (410mg, 3.611mmol) it is dissolved in THF (25mL), then sequentially adds triphenylphosphine (1.1g, 4.213mmol) and DIAD (0.84mL, 4.213mmol, 1.02g/mL), under nitrogen protection, reaction 15h is stirred at room temperature.After reaction completely, saturation food is added Salt solution (100mL), ethyl acetate extraction (50mL × 3), merge organic phase, anhydrous sodium sulfate drying, concentrated solvent.Silica gel column layer Analysis isolates and purifies (PE/EtOAc (v/v)=8/1), obtains faint yellow solid 750mg, yield：94.6%.
LC-MS:(pos.ion)m/z:264.04[M+1]+.
Step 3：Compound (R) -1- (3- (4- amino -3- (3- (the fluoro- 5- of 2- (thiazole -5- ylmethoxies) phenoxy group) propyl-s 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (150mg, 0.3767mmol) is dissolved in DMF (15mL), continuously adds 5- ((the fluoro- 3- of 4- (propyl- 2- alkynes -1- bases epoxide) benzene oxygen Base) methyl) thiazole (150mg, 0.652mmol), cuprous iodide (15mg, 0.0753mmol), triethylamine (23mg, 0.226mmol) and tetrakis triphenylphosphine palladium (22mg, 0.0188mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, are stopped Reaction, filtering, concentrated solvent, add saturated aqueous common salt (100mL), dichloromethane extraction (50mL × 3).Silica gel thin-layer analysis separation Purify (DCM/MeOH (v/v)=15/1), obtain faint yellow solid 30mg, yield：14.9%.
LC-MS:(pos.ion)m/z:534.16[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)9.09(s,1H),8.24(s,1H),8.00(s,1H),7.19(dd, J1=10.9Hz, J2=9.1Hz, 1H), 7.09 (dd, J1=7.0Hz, J2=2.5Hz, 1H), 6.85-6.69 (m, 1H), 6.65 (dt, J=8.6,2.8Hz, 1H), 6.16-6.01 (m, 1H), 5.72-5.56 (m, 1H), 5.39 (s, 2H), 5.25 (s, 2H), 4.73–4.59(m,1H),4.55–4.48(m,0.5H),4.33–4.15(m,1H),4.11–4.02(m,0.5H),3.64–3.54 (m,0.5H),3.16–3.06(m,1H),2.88–2.81(m,0.5H),2.22–2.12(m,1H),2.11–2.03(m,1H), 1.92–1.82(m,1H),1.60–1.49(m,1H).
Embodiment 54
(R) ((4- amino -3- (3- (3- hydroxyphenoxies) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] are phonetic by 3- by -1- Pyridine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 3- (propyl- 2- alkynes -1- bases epoxide) phenol
Resorcinol (600mg, 5.45mmol) is dissolved in acetone (30mL), then add Anhydrous potassium carbonate (2.3g, 16.05mmol) and 3- propargyl bromides (0.6mL, 7.0mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, be heated to reflux Reaction 24 hours.After reaction completely, filtering, concentration filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v)=60/1), Obtain weak yellow liquid 400mg, yield：49.5%.
LC-MS:(pos.ion)m/z:149.1[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (3- hydroxyphenoxies) propyl- 1- alkynes -1- bases) -1H- pyrazoles And [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (500mg, 1.256mmol) is dissolved in DMF (40mL), continuously add 3- (propyl- 2- alkynes -1- bases epoxide) phenol (280mg, 1.883mmol), cuprous iodide (48mg, 0.2511mmol), triethylamine (76mg, 0.7534mmol) and tetrakis triphenylphosphine palladium (73mg,0.0627mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filtering, concentrated solvent, adds full With saline solution (200mL), dichloromethane (80mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=35/ 1) crude product, is obtained, silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=15/1), obtains faint yellow solid 260mg, produces Rate：49.4%.
LC-MS:(pos.ion)m/z:419.18[M+1]+.
1H NMR(600MHz,DMSO-d6):δ (ppm) 9.50 (s, 1H), 8.24 (s, 1H), 7.11 (t, J=8.0Hz, 1H), 6.85-6.69 (m, 1H), 6.52 (d, J=7.7Hz, 1H), 6.46 (s, 1H), 6.42 (d, J=7.8Hz, 1H), 6.18- 6.01(m,1H),5.74–5.52(m,1H),5.09(s,2H),4.81–4.59(m,1H),4.56–4.47(m,0.5H),4.36– 4.14(m,1H),4.10–4.01(m,0.5H),3.63–3.55(m,0.5H),3.19–3.05(m,1H),2.93–2.83(m, 0.5H),2.23–2.13(m,1H),2.11–2.01(m,1H),1.93–1.82(m,1H),1.63–1.49(m,1H).
Embodiment 55
(R) -1- (3- (4- amino -3- (3- (2- (trifluoromethyl) phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3, 4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 1- (propyl- 2- alkynes -1- bases epoxide) -2- (trifluoromethyl) benzene
2- (trifluoromethyl) phenol (1g, 6.168mmol) is dissolved in acetone (40mL), then adds Anhydrous potassium carbonate (2.5g, 18.5mmol) and 3- propargyl bromides (0.8mL, 9.253mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, Heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v) are concentrated =40/1) weak yellow liquid 1.1g, yield, are obtained：89%.
LC-MS:(pos.ion)m/z:201.04[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (2- (trifluoromethyl) phenoxy group) propyl- 1- alkynes -1- bases) - 1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (140mg, 0.3516mmol) is dissolved in DMF (15mL), continuously adds 1- (propyl- 2- alkynes -1- bases epoxide) -2- (trifluoromethyl) Benzene (105mg, 0.5274mmol), cuprous iodide (14mg, 0.0703mmol), triethylamine (21mg, 0.2109mmol) and four (three Phenylphosphine) palladium (21mg, 0.0175mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentration is molten Agent, add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/ V)=35/1), crude product is obtained, then (DCM/MeOH (v/v)=18/1) is isolated and purified through silica gel thin-layer analysis, oil yellow color is obtained and consolidates Body 45mg, yield：27.72%.
LC-MS:(pos.ion)m/z:471.17[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.24(s,1H),7.69(dd,J1=18.5Hz, J2=7.9Hz, 2H), 7.53 (d, J=8.4Hz, 1H), 7.17 (t, J=7.6Hz, 1H), 6.85-6.71 (m, 1H), 6.14-6.03 (m, 1H), 5.73–5.56(m,1H),5.35(s,2H),4.69–4.58(m,1H),4.54–4.47(m,0.5H),4.32–4.13(m,1H), 4.10–4.02(m,0.5H),3.64–3.53(m,0.5H),3.18–3.07(m,1H),2.93–2.83(m,0.5H),2.21– 2.12(m,1H),2.10–2.01(m,1H),1.93–1.82(m,1H),1.61–1.49(m,1H).
Embodiment 56
(R) -1- (3- (4- amino -3- (3- (3- (trifluoromethyl) phenoxy group) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3, 4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 1- (propyl- 2- alkynes -1- bases epoxide) -3- (trifluoromethyl) benzene
3- trifloro methyl phenols (1g, 6.168mmol) are dissolved in acetone (40mL), then add Anhydrous potassium carbonate (2.5g, 18.5mmol) and 3- propargyl bromides (0.8mL, 9.253mmol, 1.38g/mL).Replace nitrogen three times, under nitrogen protection, Heating reflux reaction 24 hours.After reaction completely, filtering, filtrate, silica gel column chromatography separating purification (PE/EtOAc (v/v) are concentrated =60/1) weak yellow liquid 1.19g, yield, are obtained：96.4%.
LC-MS:(pos.ion)m/z:201.04[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (3- (trifluoromethyl) phenoxy group) propyl- 1- alkynes -1- bases) - 1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (150mg, 0.3767mmol) is dissolved in DMF (15mL), continuously adds 1- (propyl- 2- alkynes -1- bases epoxide) -3- (trifluoromethyl) Benzene (1113mg, 0.5665mmol), cuprous iodide (15mg, 0.0753mmol), triethylamine (23mg, 0.226mmol) and four (three Phenylphosphine) palladium (22mg, 0.0188mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentration is molten Agent, add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/ V)=35/1), crude product is obtained, then (DCM/MeOH (v/v)=18/1) is isolated and purified through silica gel thin-layer analysis, oil yellow color is obtained and consolidates Body 71mg, yield：40%.
LC-MS:(pos.ion)m/z:471.17[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.25 (s, 1H), 7.59 (t, J=7.4Hz, 1H), 7.47-7.40 (m, 2H), 7.36 (d, J=7.3Hz, 1H), 6.84-6.67 (m, 1H), 6.15-6.02 (m, 1H), 5.72-5.55 (m, 1H), 5.28(s,2H),4.70–4.58(m,1H),4.53–4.47(m,0.5H),4.31–4.12(m,1H),4.10–4.00(m, 0.5H),3.63–3.55(m,0.5H),3.19–3.06(m,1H),2.95–2.87(m,0.5H),2.20–2.11(m,1H), 2.10–2.02(m,1H),1.93–1.82(m,1H),1.61–1.49(m,1H).
Embodiment 57
(R) -3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl)-N- phenyl Propine acid amides
Step 1：The synthesis of compound N-phenyl propyne acid amides
Propiolic acid (0.3g, 4.28mmol) is dissolved in dichloromethane (25mL), dicyclohexyl carbon is slowly added at 0 DEG C Diimine (DCC) (0.89g, 4.28mmol), continue stirring reaction 25min, be warmed to room temperature.Sequentially add aniline (0.4mL, 36.8mmol, 1.02g/mL) and DMAP (0.01g, 0.09mmol).Heating reflux reaction 5 hours.Stopping is stirred Mix, be cooled to room temperature, diatomite filtering.Add water (60mL), dichloromethane extraction (50mL × 3).Collect organic phase, anhydrous sulphur Sour sodium is dried, and is filtered, and concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=10/1), obtains crocus liquid 0.34g, yield：54.6%.
LC-MS:(pos.ion)m/z:146.05[M+1]+.
Step 2：Compound (R) -3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidine - 3- yls)-N- phenyl propyne acid amides synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (0.18g, 0.45mmol) is dissolved in DMF (12mL), continuously adds N- phenyl propynes acid amides (0.1g, 0.68mmol), iodate Cuprous (0.018g, 0.09mmol), triethylamine (0.027g, 0.27mmol) and tetrakis triphenylphosphine palladium (0.026g, 0.02mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stop heating, are cooled to room temperature, diatomite filters, and concentration is molten Agent, saturated aqueous common salt (100mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration.Silica gel Column chromatographic isolation and purification (DCM/MeOH (v/v)=35/1), obtains yellow-brown solid 0.027g, yield：14.3%.LC-MS: (pos.ion)m/z:416.18[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 11.04 (s, 1H), 8.30 (s, 1H), 7.64 (d, J=7.9Hz, 2H),7.38(dd,J1=15.1Hz, J2=7.2Hz, 2H), 7.14 (dd, J1=15.1Hz, J2=7.7Hz, 1H), 6.86- 6.66(m,1H),6.16–6.04(m,1H),5.74–5.58(m,1H),4.77–4.66(m,1H),4.56–4.49(m,0.5H), 4.26–4.18(m,1H),4.08–4.03(m,0.5H),3.71–3.64(m,0.5H),3.23–3.16(m,1H),3.04–2.95 (m,0.5H),2.26–2.17(m,1H),2.17–2.10(m,1H),1.96–1.89(m,1H),1.65–1.54(m,1H).
Embodiment 58
(R) -1- (3- (4- amino -3- (3- phenyl propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperazines Pyridine -1- bases) propyl- 2- alkene -1- ketone
By compound (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene -1- ketone (0.18g, 0.43mmol) is dissolved in DMF (12mL), continuously add the base benzene of propyl- 2- alkynes -1 (0.075g, 0.65mmol), cuprous iodide (0.017g, 0.09mmol), triethylamine (0.026g, 0.26mmol) and tetrakis triphenylphosphine palladium (0.026g,0.02mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room temperature, diatomite mistake Filter, concentrated solvent, saturated aqueous common salt (100mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, Concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=35/1), obtains faint yellow solid 0.056g, yield： 33.3%.
LC-MS:(pos.ion)m/z:387.19[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.23 (s, 1H), 7.42 (d, J=7.5Hz, 2H), 7.38 (t, J= 7.6Hz, 2H), 7.28 (t, J=7.3Hz, 1H), 6.87-6.69 (m, 1H), 6.16-6.04 (m, 1H), 5.74-5.58 (m, 1H),4.67–4.57(m,1H),4.53–4.48(m,0.5H),4.30–4.13(m,1H),4.10–4.03(m,0.5H),4.01 (s,2H),3.64–3.56(m,0.5H),3.18–3.07(m,1H),2.95–2.84(m,0.5H),2.22–2.13(m,1H), 2.11–2.03(m,1H),1.94–1.83(m,1H),1.59–1.51(m,1H).
Embodiment 59
(R) -3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl)-N- (3- Phenoxyphenyl) propine acid amides
Step 1：The synthesis of compound N-(3- Phenoxyphenyls) propine acid amides
3- phenoxybenzamines (475mg, 2.57mmol) are dissolved in dichloromethane (20mL), then add 2- ethoxies Base -1- ethoxy carbonic acyl radical -1,2- EEDQs (EEDQ) (1.06g, 4.28mmol) and propiolic acid (200mg, 2.85mmol).Nitrogen Gas shielded, react at room temperature 24 hours.Stop stirring, add water (50mL), dichloromethane extraction (50mL × 3).Collect organic phase, Anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=10/1), obtains yellow solid 290mg, yield：42.8%.
LC-MS:(pos.ion)m/z:238.08[M+1]+.
Step 2：Compound (R) -3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidine - 3- yls)-N- (3- Phenoxyphenyls) propine acid amides synthesis
By compound (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene -1- ketone (200mg, 0.50mmol) is dissolved in DMF (12mL), continuously adds N- (3- Phenoxyphenyls) propine acid amides (214mg, 0.90mmol), cuprous iodide (20mg, 0.1mmol), triethylamine (30mg, 0.30mmol) and tetrakis triphenylphosphine palladium (30mg,0.02mmol).Under nitrogen protection, 80 DEG C of reaction 15h being heated to, stop heating, are cooled to room temperature, diatomite filters, Concentrated solvent, saturated aqueous common salt (100mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, it is dense Contracting.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains brown solid 15mg, yield：5.8%.
LC-MS:(pos.ion)m/z:508.21[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 11.09 (s, 1H), 8.30 (s, 1H), 7.43 (t, J=7.9Hz, 2H), 7.39 (d, J=5.9Hz, 2H), 7.33 (s, 1H), 7.19 (t, J=7.4Hz, 1H), 7.06 (d, J=7.9Hz, 2H), 6.81 (dt, J=5.3,4.6Hz, 1H), 6.73-6.62 (m, 1H), 6.15-6.05 (m, 1H), 5.72-5.59 (m, 1H), 4.76–4.66(m,1H),4.55–4.50(m,0.5H),4.25–4.17(m,1H),4.08–4.03(m,0.5H),3.68–3.64 (m,0.5H),3.21–3.12(m,1H),3.04–2.94(m,0.5H),2.23–2.16(m,1H),2.16–2.07(m,1H), 1.96–1.86(m,1H),1.63–1.53(m,1H).
Embodiment 60
N- (2- (4- amino -3- (3- (3- phenoxy-phenoxies) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine - 1- yls) ethyl)-N- benzylacrylamides
Step 1：The synthesis of compound 2- (benzylamino) ethanol
Benzaldehyde (2.3g, 22mmol) is dissolved in methanol (40mL), 2- amino is then slowly added into reaction solution Ethanol (1.2g, 20mmol), reaction 30min is stirred at room temperature.Sodium borohydride (450mg, 12mmol) is slowly added at 0 DEG C State in solution, be warmed to room temperature, stirring reaction 1.5 hours.Stop stirring, be diluted with water (30mL), concentrated solvent.Dichloromethane extracts Take (30mL × 3), collect organic phase, anhydrous sodium sulfate drying, filter, concentration, obtain weak yellow liquid 2.49g, yield： 84%.
LC-MS:(pos.ion)m/z:152.1[M+1]+.
Step 2：The synthesis of compound tert-butyl group benzyl (2- hydroxyethyls) carbamate
2- (benzylamino) ethanol (1g, 6.6mmol) is dissolved in dichloromethane (35mL), then added into reaction solution Enter sodium hydroxide solution (8mL, 7.9mmol), add di-tert-butyl dicarbonate (1.7mL, 7.27mmol) under ice-water bath, room temperature is stirred Mix 12 hours.Stop stirring, add saturated sodium bicarbonate solution (50mL).Dichloromethane extracts (50mL × 3), collects organic Phase, anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=8/1), is obtained faint yellow Liquid 1.5g, yield：90%.
LC-MS:(pos.ion)m/z:252.2[M+1]+.
Step 3：The synthesis of compound 2- (N- benzylacrylamides) ethyl methane sulfonate ester
T-butylbenzyl (2- hydroxyethyls) carbamate (1.5g, 6.0mmol) is dissolved in dichloromethane (50mL) In, then add triethylamine (1.3mL, 9.3mmol) and DMAP (73mg, 0.60mmol).By methylsulfonyl at 0 DEG C Chlorine (0.7mL, 9mmol) is slowly added into above-mentioned solution, continues stirring reaction 1 hour.After having reacted, unsaturated carbonate hydrogen is added Sodium solution (50mL), dichloromethane extraction (50mL × 3), collect organic phase, anhydrous sodium sulfate drying.Filtering, concentration, silicagel column Chromatography purifies (PE/EtOAc (v/v)=15/1), obtains colorless liquid product 830mg, yield：42%.
LC-MS:(pos.ion)m/z:284.1[M+1]+.
Step 4：Compound tert-butyl group (2- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) ethyl) (benzyl Base) carbamate synthesis
Iodo- 1H- pyrazolos [3, the 4-d] pyrimidine -4- amine (400mg, 1.53mmol) of 3- are dissolved in DMF (25mL), so Cesium carbonate (1g, 3.06mmol) is added afterwards, and reaction 45min is stirred at room temperature.Then tetrabutylammonium iodide is added into reaction solution (1g, 3.06mmol) and 2- (N- benzylacrylamides) ethyl methane sulfonate ester (656mg, 1.99mmol).100 DEG C are heated to, is stirred Mix reaction 13 hours.Stop stirring, be cooled to room temperature.Water (30mL) is added to dilute, ethyl acetate extraction (30mL × 3), collection has Machine phase, anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=60/1), obtains palm fibre Brown liquid 480mg, yield：59.5%.
LC-MS:(pos.ion)m/z:495.1[M+1]+.
Step 5：The synthesis of iodo- 1H- pyrazolos [3,4-d] pyrimidine -4- amine of compound 1- (2- (benzylamino) ethyl) -3-
By the tert-butyl group (2- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) ethyl) (benzyl) carbamic acid Ester (480mg, 0.97mmol) is dissolved in the mixed solution of Isosorbide-5-Nitrae-dioxane (30mL) and hydrochloric acid (25mL, 4M), is stirred at room temperature Reaction 16 hours.After reaction completely, addition sodium hydroxide solution (2M) regulation pH value of solution to 9, dichloromethane extraction (50mL × 3), organic phase anhydrous sodium sulfate drying, concentration, silica gel column chromatography separating purification (DCM/MeOH (v/v)=6/1), is obtained yellowish Color solid product 300mg, yield：78.3%.
LC-MS:(pos.ion)m/z:395.0[M+1]+.
Step 6：Compound N-(2- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) ethyl)-N- benzyls The synthesis of acrylamide
By iodo- 1H- pyrazolos [3,4-d] pyrimidine -4- amine (300mg, 0.76mmol) of 1- (2- (benzylamino) ethyl) -3- It is dissolved in dichloromethane (12mL), then adds triethylamine (0.20mL, 1.40mmol).By acryloyl chloride at 0 DEG C (0.08mL, 1mmol) is slowly added into above-mentioned solution, continues stirring reaction 15min.Stop stirring, add water (50mL) to dilute, Dichloromethane extracts (30mL × 3), collects organic phase, anhydrous sodium sulfate drying, filters, concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains faint yellow solid 150mg, yield：45.4%.
LC-MS:(pos.ion)m/z:449.1[M+1]+.
Step 7：Compound N-(2- (4- amino -3- (3- (3- phenoxy-phenoxies) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) ethyl)-N- benzylacrylamides synthesis
By N- (2- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) ethyl)-N- benzylacrylamides (60mg, 0.13mmol) is dissolved in DMF (10mL), continuously add 1- phenoxy groups -3- (propyl- 2- alkynes -1- bases epoxide) benzene (60mg, 0.26mmol), cuprous iodide (6mg, 0.026mmol), triethylamine (10mg, 0.1mmol) and tetrakis triphenylphosphine palladium (8mg, 0.069mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stop heating, are cooled to room temperature, diatomite filters, and concentration is molten Agent, saturated aqueous common salt (50mL) is added, dichloromethane extraction (30mL × 3), anhydrous sodium sulfate drying, is filtered, concentration.Silicagel column Chromatography purifies (DCM/MeOH (v/v)=30/1), obtains brown solid 20mg, yield：27.4%.
LC-MS:(pos.ion)m/z:545.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.21 (d, J=12.4Hz, 1H), 7.35 (dd, J1=16.9Hz, J2=8.4Hz, 3H), 7.26 (dd, J1=15.2Hz, J2=7.2Hz, 2H), 7.18 (d, J=7.3Hz, 1H), 7.12 (t, J= 7.3Hz,1H),7.04(dd,J1=9.0Hz, J2=8.1Hz, 3H), 6.89 (dd, J1=8.2Hz, J2=2.0Hz, 1H), 6.75 (s,1H),6.65–6.54(m,2H),6.46–6.32(m,1H),6.11–5.85(m,1H),5.64–5.39(m,1H),5.15 (s,2H),4.52–4.48(m,2H),4.48–4.43(m,2H),3.81–3.70(m,2H).
Embodiment 61
(R) -3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl)-N- (4- (trifluoromethyl) phenyl) propine acid amides
Step 1：The synthesis of compound N-(4- (trifluoromethyl) phenyl) propine acid amides
Propiolic acid (800mg, 11.42mmol) is dissolved in dichloromethane (50mL), dicyclohexyl is slowly added at 0 DEG C Carbodiimide (DCC) (2.35g, 11.42mmol), stirring reaction 30min.Then add p-trifluoromethylaniline (1.84g, 11.42mmol) and DMAP (28mg, 0.22mmol).Nitrogen is protected, heating reflux reaction 5 hours.Stop heating, be cooled to room Temperature, diatomite filtering, concentrated solvent.Add water (80mL), dichloromethane extraction (50mL × 3).Collect organic phase, anhydrous slufuric acid Sodium is dried, and is filtered, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=20/1), obtains crocus liquid 690mg, Yield：28.3%.
LC-MS:(pos.ion)m/z:214.0[M+1]+.
Step 2：Compound (R) -3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidine - 3- yls)-N- (4- (trifluoromethyl) phenyl) propine acid amides synthesis
By compound (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene -1- ketone (250mg, 0.62mmol) is dissolved in DMF (12mL), continuously adds N- (4- (trifluoromethyl) phenyl) propine acid amides (270mg, 1.25mmol), cuprous iodide (24mg, 0.12mmol), triethylamine (38mg, 0.37mmol) and four (triphenylphosphines) Palladium (37mg, 0.03mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room temperature, diatomite mistake Filter, concentrated solvent, saturated aqueous common salt (100mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, Concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=35/1), obtains yellow-brown solid 11mg, yield：4.9%.
LC-MS:(pos.ion)m/z:484.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 11.37 (s, 1H), 8.31 (s, 1H), 7.86 (d, J=8.5Hz, 2H), 7.76 (d, J=8.6Hz, 2H), 6.86-6.69 (m, 1H), 6.16-6.05 (m, 1H), 5.73-5.60 (m, 1H), 4.79- 4.67(m,1H),4.57–4.52(m,0.5H),4.26–4.18(m,1H),4.09–4.04(m,0.5H),3.70–3.63(m, 0.5H),3.21–3.15(m,1H),3.00(s,0.5H),2.26–2.18(m,1H),2.17–2.10(m,1H),1.96–1.89 (m,1H),1.65–1.56(m,1H).
Embodiment 62
(R) -3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl)-N- benzyls Propine acid amides
Step 1：The synthesis of compound N-benzyl propine acid amides
Propiolic acid (600mg, 8.56mmol) is dissolved in dichloromethane (50mL), dicyclohexyl is slowly added at 0 DEG C Carbodiimide (DCC) (1.76g, 8.56mmol), continue stirring reaction 25min, be warmed to room temperature.Sequentially add benzylamine (1.1g, 10.28mmol) and DMAP (20mg, 0.17mmol).Heating reflux reaction 5 hours.Stop stirring, be cooled to room Temperature, diatomite filtering.Add water (60mL), dichloromethane extraction (50mL × 3).Collect organic phase, anhydrous sodium sulfate drying, mistake Filter, concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=7/1), obtains faint yellow solid 470mg, yield： 34.7%.
LC-MS:(pos.ion)m/z:160.1[M+1]+.
Step 2：Compound (R) -3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidine - 3- yls)-N- benzyl propine acid amides synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (500mg, 1.26mmol) is dissolved in DMF (15mL), continuously adds N- benzyl propine acid amides (400mg, 2.51mmol), iodate Cuprous (47mg, 0.25mmol), triethylamine (80mg, 0.75mmol) and tetrakis triphenylphosphine palladium (72mg, 0.06mmol).Nitrogen Under protection, 80 DEG C of reaction 15h are heated to, stop heating, be cooled to room temperature, diatomite filtering, concentrated solvent, add saturated common salt Water (100mL), dichloromethane extraction (60mL × 3), anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains faint yellow solid 115mg, yield：21%.LC-MS:(pos.ion)m/z:430.2 [M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)9.54(s,1H),8.29(s,1H),7.51–7.15(m,5H), 6.86–6.66(m,1H),6.18–6.02(m,1H),5.75–5.56(m,1H),4.76–4.63(m,1H),4.56–4.48(m, 0.5H), 4.42 (d, J=4.6Hz, 2H), 4.26-4.17 (m, 1H), 4.10-4.01 (m, 0.5H), 3.70-3.59 (m, 0.5H),3.21–3.13(m,1H),2.99–2.90(m,0.5H),2.26–2.15(m,1H),2.15–2.05(m,1H),1.96– 1.86(m,1H),1.68–1.51(m,1H).
Embodiment 63
(R) -3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl)-N- (pyrroles Pyridine -2- ylmethyls) propine acid amides
Step 1：The synthesis of compound N-(pyridine -2- ylmethyls) propine acid amides
Propiolic acid (500mg, 7.14mmol) is dissolved in dichloromethane (50mL), dicyclohexyl is slowly added at 0 DEG C Carbodiimide (DCC) (1.47g, 7.14mmol), continue stirring reaction 25min, be warmed to room temperature.Sequentially add 2- aminomethyl-pyridines (920mg, 8.56mmol) and DMAP (17mg, 0.14mmol).Heating reflux reaction 5 hours.Stop stirring, it is cold But to room temperature, diatomite filtering.Add water (60mL), dichloromethane extraction (50mL × 3).Collect organic phase, anhydrous sodium sulfate Dry, filter, concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=1/1).Yellow-brown solid 547mg is obtained, is produced Rate：47.8%.
LC-MS:(pos.ion)m/z:161.1[M+1]+.
Step 2：Compound (R) -3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidine - 3- yls)-N- (pyridine -2- ylmethyls) propine acid amides synthesis
By compound (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene -1- ketone (140mg, 0.35mmol) is dissolved in DMF (12mL), continuously adds N- (pyridine -2- ylmethyls) propine acid amides (112mg, 0.70mmol), cuprous iodide (14mg, 0.07mmol), triethylamine (20mg, 0.21mmol) and four (triphenylphosphines) Palladium (21mg, 0.017mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room temperature, diatomite mistake Filter, concentrated solvent, saturated aqueous common salt (100mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, Concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=10/1), obtains brown solid 12mg, yield：7.9%.
LC-MS:(pos.ion)m/z:431.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)8.53(s,1H),8.34(s,1H),8.18(s,1H),7.70(d,J =13.5Hz, 1H), 6.95-6.81 (m, 1H), 6.77-6.62 (m, 1H), 6.39-6.30 (m, 1H), 6.19-6.06 (m, 1H), 5.58-5.48 (m, 1H), 5.28 (d, J=5.6Hz, 2H), 4.79-4.65 (m, 1H), 4.61-4.54 (m, 0.5H), 4.27- 4.18(m,1H),4.11–4.05(m,0.5H),3.96–3.87(m,1H),3.74–3.63(m,1H),2.34–2.25(m,1H), 2.20–2.12(m,1H),2.00–1.93(m,1H),1.67–1.60(m,1H).
Embodiment 64
(R) -3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl)-N- (3- Luorobenzyl) propine acid amides
Step 1：The synthesis of compound N-(3- luorobenzyls) propine acid amides
Propiolic acid (500mg, 7.14mmol) is dissolved in dichloromethane (50mL), dicyclohexyl is slowly added at 0 DEG C Carbodiimide (DCC) (1.47g, 7.14mmol), continue stirring reaction 25min, be warmed to room temperature.Sequentially add 3- fluorin benzyl amines (1.09g, 8.56mmol) and DMAP (17mg, 0.14mmol).Heating reflux reaction 5 hours.Stop stirring, it is cold But to room temperature, diatomite filtering.Add water (60mL), dichloromethane extraction (50mL × 3).Collect organic phase, anhydrous sodium sulfate Dry, filter, concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=6/1), obtain crocus solid 711mg, produce Rate：56.2%.
LC-MS:(pos.ion)m/z:178.1[M+1]+.
Step 2：Compound (R) -3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidine - 3- yls)-N- (3- luorobenzyls) propine acid amides synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (140mg, 0.35mmol) is dissolved in DMF (12mL), continues to add N- (3- luorobenzyls) propine acid amides (125g, 0.70mmol), Cuprous iodide (14mg, 0.07mmol), triethylamine (20mg, 0.21mmol) and tetrakis triphenylphosphine palladium (21mg, 0.017mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stop heating, are cooled to room temperature, diatomite filters, and concentration is molten Agent, saturated aqueous common salt (100mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration.Silica gel Column chromatographic isolation and purification (DCM/MeOH (v/v)=35/1), obtains faint yellow solid 18mg, yield：11.4%.
LC-MS:(pos.ion)m/z:448.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)9.57(s,1H),8.29(s,1H),7.42(dd,J1=14.1Hz, J2=7.3Hz, 1H), 7.22-7.08 (m, 3H), 6.85-6.67 (m, 1H), 6.17-6.03 (m, 1H), 5.76-5.54 (m, 1H), 4.76-4.64 (m, 1H), 4.57-4.49 (m, 0.5H), 4.44 (d, J=5.4Hz, 2H), 4.28-4.16 (m, 1H), 4.11–4.00(m,0.5H),3.71–3.59(m,0.5H),3.22–3.13(m,1H),3.03–2.92(m,0.5H),2.26– 2.17(m,1H),2.15–2.05(m,1H),1.97–1.86(m,1H),1.66–1.52(m,1H).
Embodiment 65
(R) -3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl)-N- (2- Luorobenzyl) propine acid amides
Step 1：The synthesis of compound N-(2- luorobenzyls) propine acid amides
Propiolic acid (500mg, 7.14mmol) is dissolved in dichloromethane (50mL), dicyclohexyl is slowly added at 0 DEG C Carbodiimide (DCC) (1.47g, 7.14mmol), continue stirring reaction 25min, be warmed to room temperature.Sequentially add 2- fluorin benzyl amines (1.09g, 8.56mmol) and DMAP (17mg, 0.14mmol).Heating reflux reaction 5 hours.Stop stirring, it is cold But to room temperature, diatomite filtering.Add water (60mL), dichloromethane extraction (50mL × 3).Collect organic phase, anhydrous sodium sulfate Dry, filter, concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=6/1), obtain crocus solid 531mg, produce Rate：42%.
LC-MS:(pos.ion)m/z:178.1[M+1]+.
Step 2：Compound (R) -3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidine - 3- yls)-N- (2- luorobenzyls) propine acid amides synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (150mg, 0.37mmol) is dissolved in DMF (12mL), continuously add N- (2- luorobenzyls) propine acid amides (100mg, 0.56mmol), cuprous iodide (14mg, 0.075mmol), triethylamine (38mg, 0.37mmol) and tetrakis triphenylphosphine palladium (21mg,0.018mmol).Under nitrogen protection, 80 DEG C of reaction 15h being heated to, stop heating, are cooled to room temperature, diatomite filters, Concentrated solvent, saturated aqueous common salt (100mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, it is dense Contracting.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains yellow-brown solid 40mg, yield：23.7%.
LC-MS:(pos.ion)m/z:448.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 9.55 (t, J=5.5Hz, 1H), 8.29 (s, 1H), 7.42 (t, J= 7.6Hz,1H),7.39–7.35(m,1H),7.26–7.19(m,2H),6.84–6.70(m,1H),6.17–6.02(m,1H), 5.73-5.56 (m, 1H), 4.75-4.66 (m, 1H), 4.55-4.49 (m, 0.5H), 4.46 (d, J=5.7Hz, 2H), 4.26- 4.17(m,1H),4.09–4.03(m,0.5H),3.70–3.60(m,0.5H),3.22–3.15(m,1H),3.01–2.92(m, 0.5H),2.24–2.16(m,1H),2.16–2.08(m,1H),1.95–1.88(m,1H),1.63–1.53(m,1H).
Embodiment 66
(R) -3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl)-N- (3- (trifluoromethyl) benzyl) propine acid amides
Step 1：The synthesis of compound N-(3- (trifluoromethyl) benzyl) propine acid amides
Propiolic acid (400mg, 5.71mmol) is dissolved in dichloromethane (50mL), dicyclohexyl is slowly added at 0 DEG C Carbodiimide (DCC) (1.18g, 5.71mmol), continue stirring reaction 25min, be warmed to room temperature.Sequentially add 3- trifluoromethyl benzyls Amine (1.22g, 6.85mmol) and DMAP (13mg, 0.11mmol), heating reflux reaction 10 hours.Stopping is stirred Mix, be cooled to room temperature, diatomite filtering.Add water (60mL), dichloromethane extraction (50mL × 3).Collect organic phase, anhydrous sulphur Sour sodium is dried, and is filtered, and concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=6/1), obtains crocus solid 610mg, yield：47.2%.
LC-MS:(pos.ion)m/z:228.1[M+1]+.
Step 2：Compound (R) -3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidine - 3- yls)-N- (3- (trifluoromethyl) benzyl) propine acid amides synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (170mg, 0.43mmol) is dissolved in DMF (12mL), continuously add N- (3- (trifluoromethyl) benzyl) propine acid amides (150mg, 0.64mmol), cuprous iodide (16mg, 0.085mmol), triethylamine (43mg, 0.43mmol) and tetrakis triphenylphosphine palladium (24mg,0.02mmol).Under nitrogen protection, 80 DEG C of reaction 15h being heated to, stop heating, are cooled to room temperature, diatomite filters, Concentrated solvent, saturated aqueous common salt (100mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, it is dense Contracting.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains yellow-brown solid 58mg, yield：27.3%.
LC-MS:(pos.ion)m/z:498.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 9.63 (t, J=5.7Hz, 1H), 8.29 (s, 1H), 7.70-7.60 (m,4H),6.85–6.69(m,1H),6.16–6.05(m,1H),5.72–5.59(m,1H),4.75–4.65(m,1H),4.52 (d, J=5.9Hz, 2H), 4.51-4.47 (m, 0.5H), 4.26-4.18 (m, 1H), 4.11-4.01 (m, 0.5H), 3.69-3.61 (m,0.5H),3.21–3.15(m,1H),3.02–2.93(m,0.5H),2.25–2.15(m,1H),2.15–2.09(m,1H), 1.96–1.87(m,1H),1.63–1.54(m,1H).
Embodiment 67
(R) -3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl)-N- (3- Methoxy-benzyl) propine acid amides
Step 1：The synthesis of compound N-(3- methoxy-benzyls) propine acid amides
3- methoxybenzylamines (600mg, 4.37mmol) are dissolved in dichloromethane (40mL), then add 2- ethoxies Base -1- ethoxy carbonic acyl radical -1,2- EEDQs (EEDQ) (1.62g, 6.56mmol), under nitrogen protection, it is slowly added to propiolic acid (400mg,5.25mmol).Room temperature reaction 15 hours, after reaction completely, add water (80mL), watery hydrochloric acid regulation pH to 3.Dichloro Methane extracts (60mL × 3), collects organic phase, anhydrous sodium sulfate drying, filters, concentration.Silica gel column chromatography separating purification (PE/ EtOAc (v/v)=6/1), obtain crocus liquid 800mg, yield：96%.
LC-MS:(pos.ion)m/z:190.1[M+1]+.
Step 2：Compound (R) -3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidine - 3- yls)-N- (3- methoxy-benzyls) propine acid amides synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (180mg, 0.45mmol) is dissolved in DMF (12mL), continuously add N- (3- methoxy-benzyls) propine acid amides (130mg, 0.68mmol), cuprous iodide (18mg, 0.09mmol), triethylamine (45mg, 0.45mmol) and tetrakis triphenylphosphine palladium (27mg, 0.023mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stop heating, are cooled to room temperature, diatomite filters, and concentration is molten Agent, saturated aqueous common salt (100mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration.Silica gel Column chromatographic isolation and purification (DCM/MeOH (v/v)=40/1), obtains brown solid 48mg, yield：23.1%.
LC-MS:(pos.ion)m/z:460.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 9.53 (s, 1H), 8.29 (s, 1H), 7.29 (t, J=7.7Hz, 1H), 6.94-6.89 (m, 2H), 6.86 (d, J=8.7Hz, 2H), 6.73-6.62 (m, 1H), 6.18-6.03 (m, 1H), 5.74- 5.57 (m, 1H), 4.76-4.65 (m, 1H), 4.55-4.48 (m, 0.5H), 4.39 (d, J=5.4Hz, 2H), 4.27-4.17 (m, 1H),4.08–4.02(m,0.5H),3.76(s,3H),3.67–3.63(m,0.5H),3.22–3.15(m,1H),3.00–2.91 (m,0.5H),2.25–2.15(m,1H),2.15–2.07(m,1H),1.96–1.86(m,1H),1.64–1.52(m,1H).
Embodiment 68
(R) -1- (3- (4- amino -3- (3- (benzyloxy) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- Base) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound ((propyl- 2- alkynes -1- bases epoxide) methyl) benzene
Phenmethylol (700mg, 6.47mmol) is dissolved in THF (35mL), sodium hydride is slowly added at -20 DEG C (360mg, 7.77mmol), it is warmed to room temperature stirring 20min.3- propargyl bromides (1.0g, 7.77mmol), nitrogen are slowly added at 0 DEG C Protection, react at room temperature 24 hours.Stop stirring, diatomite filtering, concentrated solvent.Add water (60mL), ethyl acetate extraction (50mL×3).Organic phase is collected, anhydrous sodium sulfate drying, is filtered, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/ V)=60/1), weak yellow liquid 490mg, yield are obtained：51.7%.1H NMR(400MHz,DMSO-d6):δ(ppm)7.43– 7.24 (5H, m), 4.53 (2H, s), 4.18 (2H, d, J=2.4Hz), 3.46 (1H, t, J=2.4Hz)
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (benzyloxy) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3, 4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (180mg, 0.45mmol) is dissolved in DMF (12mL), continuously add ((propyl- 2- alkynes -1- bases epoxide) methyl) benzene (120mg, 0.81mmol), cuprous iodide (17mg, 0.09mmol), triethylamine (30mg, 0.30mmol) and tetrakis triphenylphosphine palladium (26mg, 0.022mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stop heating, are cooled to room temperature, diatomite filters, and concentration is molten Agent, saturated aqueous common salt (100mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration.Silica gel Column chromatographic isolation and purification (DCM/MeOH (v/v)=50/1), obtains brown solid 160mg, yield：84.9%.
LC-MS:(pos.ion)m/z:417.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.25 (s, 1H), 7.38 (d, J=4.3Hz, 4H), 7.34-7.29 (m,1H),6.86–6.71(m,1H),6.17–6.03(m,1H),5.74–5.58(m,1H),4.73–4.64(m,1H),4.63 (s,2H),4.55(s,2H),4.53–4.50(m,0.5H),4.30–4.16(m,1H),4.10–4.03(m,0.5H),3.68– 3.58(m,0.5H),3.20–3.11(m,1H),2.96–2.88(m,0.5H),2.26–2.15(m,1H),2.13–2.05(m, 1H),1.94–1.85(m,1H),1.62–1.52(m,1H).
Embodiment 69
(R) -1- (3- (4- amino -3- (3- (benzylamino) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- Base) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound N-benzyl propyl- 2- alkynes -1- amine
3- propargyl bromides (800mg, 6.72mmol) are dissolved in toluene (0.5mL), are slowly dropped to benzylamine at room temperature In (4.5mL, 40.35mmol).Nitrogen is protected, and is reacted at room temperature 24 hours.Stop stirring, add hydrochloric acid solution (2M, 50mL), second Acetoacetic ester extracts (50mL × 3).Organic phase is collected, anhydrous sodium sulfate drying, is filtered, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=8/1), obtains weak yellow liquid 550mg, yield：56%.
LC-MS:(pos.ion)m/z:146.1[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (benzylamino) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (170mg, 0.43mmol) is dissolved in DMF (12mL), continuously adds N- benzyl propyl- 2- alkynes -1- amine (115mg, 0.77mmol), Cuprous iodide (16mg, 0.085mmol), triethylamine (30mg, 0.30mmol) and tetrakis triphenylphosphine palladium (24mg, 0.021mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stop heating, are cooled to room temperature, diatomite filters, and concentration is molten Agent, saturated aqueous common salt (100mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration.Silica gel Column chromatographic isolation and purification (DCM/MeOH (v/v)=50/1), obtains brown solid 103mg, yield：58%.
LC-MS:(pos.ion)m/z:416.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.25 (s, 1H), 7.49-7.27 (m, 5H), 7.24 (t, J= 6.8Hz,1H),6.87–6.69(m,1H),6.18–6.02(m,1H),5.74–5.56(m,1H),4.71–4.58(m,1H), 4.56–4.47(m,0.5H),4.34–4.12(m,1H),4.09–4.03(m,0.5H),3.96–3.75(m,2H),3.74–3.63 (m,2H),3.62–3.57(m,0.5H),3.20–3.10(m,1H),2.97–2.87(m,0.5H),2.24–2.15(m,1H), 2.12–2.04(m,1H),1.95–1.85(m,1H),1.63–1.50(m,1H).
Embodiment 70
(R) -1- (3- (4- amino -3- (3- hydroxy-3-methyl butyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine - 1- yls) piperidin-1-yl) propyl- 2- alkene -1- ketone
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (150mg, 0.38mmol) is dissolved in DMF (12mL), continuously adds 3- methyl -3- butynols (56mg, 0.68mmol), iodate Cuprous (14mg, 0.075mmol), triethylamine (23mg, 0.23mmol) and tetrakis triphenylphosphine palladium (21mg, 0.019mmol).Nitrogen Under gas shielded, 80 DEG C of reaction 15h are heated to, stop heating, be cooled to room temperature, diatomite filtering, concentrated solvent, add saturation food Salt solution (100mL), dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains brown solid 120mg, yield：89.8%.LC-MS:(pos.ion)m/z:355.2 [M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)8.24(s,1H),6.89–6.65(m,1H),6.17–6.02(m, 1H),5.81(s,1H),5.73–5.56(m,1H),4.73–4.56(m,1H),4.55–4.48(m,0.5H),4.35–4.12(m, 1H),4.11–4.02(m,0.5H),3.70–3.53(m,0.5H),3.18–3.06(m,1H),2.95–2.82(m,0.5H), 2.24–2.12(m,1H),2.11–2.01(m,1H),1.93–1.82(m,1H),1.63–1.54(m,1H),1.51(s,6H).
Embodiment 71
(R) -1- (3- (4- amino -3- (3- (benzylamino) -3- methyl butyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] Pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 2- methyl butyl- 3- alkynes -2- yl acetates
Acetic anhydride (2.91g, 28.53mmol) and magnesium perchlorate (80mg, 0.36mmol) are added to 50mL round-bottomed flasks In, then 3- methyl -3- butynols (2.0g, 23.78mmol) are slowly dropped in above-mentioned solution, reacted at room temperature 1.5 hours. Stop stirring, add the aqueous solution (80mL), dichloromethane extraction (50mL × 3).Collect organic phase, anhydrous sodium sulfate drying, mistake Filter, concentration.Obtain weak yellow liquid 2.07g, yield：63.5%.
LC-MS:(pos.ion)m/z:127.1[M+1]+.
Step 2：The synthesis of compound (((2- methyl butyl- 3- alkynes -2- bases) epoxide) methyl) benzene
2- methyl butyl- 3- alkynes -2- yl acetates (1g, 7.93mmol) and stannous chloride (40mg, 0.40mmol) are dissolved In THF (25mL), benzylamine (1.75mL, 15.86mmol) is slowly added into above-mentioned solution at room temperature.Nitrogen is protected, and is added Hot to 70 DEG C are reacted 3 hours.Stop heating, be cooled to room temperature.Add water (100mL), dichloromethane extraction (50mL × 3).Receive Collect organic phase, anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=20/1), is obtained To weak yellow liquid 750mg, yield：54.6%.
LC-MS:(pos.ion)m/z:175.1[M+1]+.
Step 3：Compound (R) -1- (3- (4- amino -3- (3- (benzylamino) -3- methyl butyl- 1- alkynes -1- bases) -1H- Pyrazolo [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (150mg, 0.37mmol) is dissolved in DMF (12mL), continuously adds (((2- methyl butyl- 3- alkynes -2- bases) epoxide) methyl) benzene (118mg, 0.68mmol), cuprous iodide (14mg, 0.075mmol), triethylamine (23mg, 0.23mmol) and four (triphenylphosphines) Palladium (21mg, 0.019mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room temperature, diatomite mistake Filter, concentrated solvent, saturated aqueous common salt (100mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, Concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains brown solid 108mg, yield：64.6%.
LC-MS:(pos.ion)m/z:444.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.27 (s, 1H), 7.38 (d, J=7.2Hz, 2H), 7.31 (t, J= 7.3Hz, 2H), 7.23 (t, J=6.9Hz, 1H), 6.89-6.68 (m, 1H), 6.19-6.05 (m, 1H), 5.75-5.58 (m, 1H),4.75–4.59(m,1H),4.58–4.48(m,0.5H),4.36–4.13(m,1H),4.11–4.02(m,0.5H),3.95– 3.75(m,2H),3.68–3.58(m,0.5H),3.20–3.11(m,1H),2.92–2.85(m,0.5H),2.26–2.15(m, 1H),2.13–2.04(m,1H),1.93–1.85(m,1H),1.64–1.53(m,1H),1.48(s,6H).
Embodiment 72
(R) ((4- amino -3- (3- (benzyloxy) -3- methyl butyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] are phonetic by 3- by -1- Pyridine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound (((2- methyl butyl- 3- alkynes -2- bases) epoxide) methyl) benzene
3- methyl -3- butynols (600mg, 7.13mmol) are dissolved in anhydrous THF (50mL), under condition of ice bath slowly Sodium hydride (342mg, 8.56mmol) is added, is warmed to room temperature, continues stirring 1 hour.Then sequentially add benzyl bromine (1.02mL, 8.56mmol) and tetrabutylammonium iodide (26mg, 0.07mmol).Nitrogen is protected, and is reacted at room temperature 24 hours.Stop stirring, add Water (60mL), dichloromethane extraction (50mL × 3).Organic phase is collected, anhydrous sodium sulfate drying, is filtered, concentration.Silica gel column chromatography (PE/EtOAc (v/v)=6/1) is isolated and purified, obtains weak yellow liquid 1.05g, yield：84.5%.
LC-MS:(pos.ion)m/z:175.1[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (benzyloxy) -3- methyl butyl- 1- alkynes -1- bases) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (150mg, 0.38mmol) is dissolved in DMF (12mL), continuously adds (((2- methyl butyl- 3- alkynes -2- bases) epoxide) methyl) benzene (118mg, 0.68mmol), cuprous iodide (14mg, 0.075mmol), triethylamine (23mg, 0.23mmol) and four (triphenylphosphines) Palladium (21mg, 0.019mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room temperature, diatomite mistake Filter, concentrated solvent, saturated aqueous common salt (100mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, Concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains brown viscous thing 140mg, yield：83.6%.
LC-MS:(pos.ion)m/z:445.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)8.27(s,1H),7.41–7.30(m,4H),7.30–7.19(m, 1H),6.88–6.67(m,1H),6.21–6.00(m,1H),5.73–5.54(m,1H),4.67(s,2H),4.66–4.59(m, 1H),4.58–4.49(m,0.5H),4.35–4.15(m,1H),4.14–3.96(m,0.5H),3.73–3.55(m,0.5H), 3.22–3.13(m,1H),2.96–2.83(m,0.5H),2.28–2.14(m,1H),2.13–2.02(m,1H),1.95–1.83 (m,1H),1.66(s,6H),1.59–1.49(m,1H).
Embodiment 73
(R)-N- (3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl-s 2- alkynes -1- bases) benzamide
Step 1：The synthesis of compound N-(propyl- 2- alkynes -1- bases) benzamide
Propargylamine (500mg, 9.08mmol) and triethylamine (1.53mL, 10.89mmol) are dissolved in dichloromethane In (25mL), it is slowly added in chlorobenzoyl chloride (1.5g, 9.99mmol), is warmed to room temperature under condition of ice bath, reacts at room temperature 1 hour. Stop stirring, add water (60mL), dichloromethane extraction (50mL × 3).Organic phase is collected, anhydrous sodium sulfate drying, is filtered, it is dense Contracting.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=6/1), obtains white solid 843mg, yield：58.3%.
LC-MS:(pos.ion)m/z:160.1[M+1]+.
Step 2：((1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] are phonetic by 3- by compound (R)-N- Pyridine -3- bases) propyl- 2- alkynes -1- bases) benzamide synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (160mg, 0.40mmol) is dissolved in DMF (15mL), continuously add N- (propyl- 2- alkynes -1- bases) benzamide (115mg, 0.72mmol), cuprous iodide (15mg, 0.080mmol), triethylamine (24mg, 0.24mmol) and tetrakis triphenylphosphine palladium (23mg,0.020mmol).Under nitrogen protection, 80 DEG C of reaction 15h being heated to, stop heating, are cooled to room temperature, diatomite filters, Concentrated solvent, saturated aqueous common salt (80mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration. Silica gel column chromatography separating purification (DCM/MeOH (v/v)=45/1), obtains brown solid 140mg, yield：81.1%.
LC-MS:(pos.ion)m/z:430.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ (ppm) 9.16 (s, 1H), 8.23 (s, 1H), 7.90 (d, J=5.1Hz, 2H), 7.55 (d, J=5.3Hz, 1H), 7.53-7.34 (m, 2H), 6.88-6.68 (m, 1H), 6.21-6.00 (m, 1H), 5.81- 5.52(m,1H),4.80–4.56(m,1H),4.56–4.45(m,0.5H),4.38(s,2H),4.30–4.12(m,1H),4.10– 3.93(m,0.5H),3.68–3.53(m,0.5H),3.18–3.07(m,1H),2.97–2.83(m,0.5H),2.25–2.10(m, 1H),2.10–1.98(m,1H),1.94–1.79(m,1H),1.67–1.44(m,1H).
Embodiment 74
(R)-N- (3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl-s 2- alkynes -1- bases) benzsulfamide
Step 1：The synthesis of compound N-(propyl- 2- alkynes -1- bases) benzsulfamide
Propargylamine (375mg, 6.79mmol) and DIPEA (3.78mL, 22.65mmol) are dissolved in dichloromethane (50mL) In, it is slowly added in benzene sulfonyl chloride (1g, 5.66mmol), is warmed to room temperature under condition of ice bath, reacts at room temperature 2 hours.Stop stirring, Add water (60mL), dichloromethane extraction (50mL × 3).Organic phase is collected, anhydrous sodium sulfate drying, is filtered, concentration.Silicagel column Chromatography purifies (PE/EtOAc (v/v)=6/1), obtains pale yellow oil 701mg, yield：63.5%.
LC-MS:(pos.ion)m/z:196.0[M+1]+.
Step 2：((1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] are phonetic by 3- by compound (R)-N- Pyridine -3- bases) propyl- 2- alkynes -1- bases) benzsulfamide synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (150mg, 0.37mmol) is dissolved in DMF (12mL), continuously add N- (propyl- 2- alkynes -1- bases) benzsulfamide (132mg, 0.68mmol), cuprous iodide (14mg, 0.075mmol), triethylamine (23mg, 0.23mmol) and tetrakis triphenylphosphine palladium (21mg,0.019mmol).Under nitrogen protection, 80 DEG C of reaction 15h being heated to, stop heating, are cooled to room temperature, diatomite filters, Concentrated solvent, saturated aqueous common salt (80mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration. Silica gel column chromatography separating purification (DCM/MeOH (v/v)=50/1), obtains brown solid 138mg, yield：78.7%.
LC-MS:(pos.ion)m/z:466.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)8.30(s,1H),8.23(s,1H),7.94–7.81(m,2H), 7.60–7.43(m,3H),6.88–6.64(m,1H),6.19–5.99(m,1H),5.77–5.55(m,1H),4.77–4.54(m, 1H), 4.54-4.43 (m, 0.5H), 4.37-4.15 (m, 1H), 4.15-4.10 (m, 0.5H), 4.07 (d, J=3.5Hz, 2H), 3.67–3.54(m,0.5H),3.16–3.05(m,1H),3.01–2.88(m,0.5H),2.22–2.11(m,1H),2.11–2.01 (m,1H),1.96–1.84(m,1H),1.64–1.48(m,1H).
Embodiment 75
(R)-N- (4- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) -2- Methyl butyl- 3- alkynes -2- bases) benzsulfamide
Step 1：The synthesis of compound N-(2- methyl butyl- 3- alkynes -2- bases) benzsulfamide
By 2- methyl -3- crotonylenes-amine (250mg, 3.0mmol), triethylamine (0.5mL, 3.31mmol) and DMAP (3mg, 0.03mmol) it is dissolved in dichloromethane (45mL), is slowly added under condition of ice bath in benzene sulfonyl chloride (585mg, 3.31mmol), It is warmed to room temperature, reacts at room temperature 6 hours.Stop stirring, add water (60mL) and be quenched, dichloromethane extraction (50mL × 3).Collection has Machine phase, anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=10/1), is obtained white Color solid 400mg, yield：59.5%.
LC-MS:(pos.ion)m/z:224.1[M+1]+.
Step 2：((1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] are phonetic by 4- by compound (R)-N- Pyridine -3- bases) -2- methyl butyl- 3- alkynes -2- bases) benzsulfamide synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.30mmol) is dissolved in DMF (12mL), continuously adds N- (2- methyl butyl- 3- alkynes -2- bases) benzsulfamide (100mg, 0.45mmol), cuprous iodide (11mg, 0.06mmol), triethylamine (18mg, 0.18mmol) and four (triphenylphosphines) Palladium (18mg, 0.015mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room temperature, diatomite mistake Filter, concentrated solvent, saturated aqueous common salt (100mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, Concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains faint yellow solid 105mg, yield： 70.59%.
LC-MS:(pos.ion)m/z:494.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.38(s,1H),8.25(s,1H),7.90–7.80(m,2H), 7.47–7.34(m,3H),6.89–6.67(m,1H),6.18–6.04(m,1H),5.75–5.59(m,1H),4.71–4.56(m, 1H),4.55–4.48(m,0.5H),4.36–4.13(m,1H),4.11–4.05(m,0.5H),3.63–3.54(m,0.5H), 3.13–3.03(m,1H),2.93–2.84(m,0.5H),2.22–2.11(m,1H),2.10–2.01(m,1H),1.92–1.83 (m,1H),1.63–1.56(m,1H),1.54(s,6H).
Embodiment 76
(R)-N- (3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl-s 2- alkynes -1- bases) -4- methyl benzenesulfonamides
Step 1：The synthesis of compound 4- methyl-N- (propyl- 2- alkynes -1- bases) benzsulfamide
Propargylamine (200mg, 3.63mmol), TEA (0.56mL, 3.99mmol) and DMAP (5mg, 0.04mmol) are dissolved In dichloromethane (50mL).P-methyl benzene sulfonic chloride (760mg, 3.99mmol) is slowly added under condition of ice bath, is warmed to room temperature, Room temperature reaction 8 hours.Stop stirring, add water (80mL) and be quenched, dichloromethane extraction (50mL × 3).Organic phase is collected, it is anhydrous Sodium sulphate is dried, and is filtered, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=10/1), obtains faint yellow solid 600mg, yield：78.9%.
LC-MS:(pos.ion)m/z:210.1[M+1]+.
Step 2：((1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] are phonetic by 3- by compound (R)-N- Pyridine -3- bases) propyl- 2- alkynes -1- bases) -4- methyl benzenesulfonamides synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (150mg, 0.38mmol) is dissolved in DMF (15mL), continuously adds 4- methyl-N- (propyl- 2- alkynes -1- bases) benzsulfamide (141mg, 0.68mmol), cuprous iodide (14mg, 0.075mmol), triethylamine (23mg, 0.23mmol) and four (triphenylphosphines) Palladium (21mg, 0.019mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room temperature, diatomite mistake Filter, concentrated solvent, saturated aqueous common salt (80mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, it is dense Contracting.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=45/1), obtains brown solid 122mg, yield：67.5%.
LC-MS:(pos.ion)m/z:480.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.24 (s, 1H), 8.19 (s, 1H), 7.73 (d, J=7.7Hz, 2H),7.31–7.18(m,2H),6.90–6.65(m,1H),6.21–5.99(m,1H),5.74–5.54(m,1H),4.77–4.55 (m, 1H), 4.55-4.45 (m, 0.5H), 4.35-4.11 (m, 1H), 4.11-4.07 (m, 0.5H), 4.04 (d, J=5.0Hz, 2H),3.63–3.54(m,0.5H),3.13–3.05(m,1H),2.97–2.86(m,0.5H),2.20–2.15(m,1H),2.13 (d, J=23.6Hz, 3H), 2.08-2.01 (m, 1H), 1.94-1.83 (m, 1H), 1.64-1.49 (m, 1H)
Embodiment 77
(R)-N- (3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl-s 2- alkynes -1- bases) -3- fluorobenzenesulfonamides
Step 1：The synthesis of the fluoro- N- of compound 3- (propyl- 2- alkynes -1- bases) benzsulfamide
Propargylamine (200mg, 3.63mmol), TEA (0.56mL, 3.99mmol) and DMAP (5mg, 0.04mmol) are dissolved In dichloromethane (45mL).3- fluorophenylsulfonyl chlorides (0.55mL, 3.99mmol) are slowly added under condition of ice bath, are warmed to room temperature, Room temperature reaction 8 hours.Stop stirring, add water (80mL) and be quenched, dichloromethane extraction (50mL × 3).Organic phase is collected, it is anhydrous Sodium sulphate is dried, and is filtered, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=10/1), obtains faint yellow solid 610mg, yield：78.7%.
LC-MS:(pos.ion)m/z:214.0[M+1]+.
Step 2：((1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] are phonetic by 3- by compound (R)-N- Pyridine -3- bases) propyl- 2- alkynes -1- bases) -3- fluorobenzenesulfonamides synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.30mmol) is dissolved in DMF (15mL), continuously adds the fluoro- N- of 3- (propyl- 2- alkynes -1- bases) benzsulfamide (100mg, 0.45mmol), cuprous iodide (11mg, 0.060mmol), triethylamine (18mg, 0.18mmol) and four (triphenylphosphines) Palladium (18mg, 0.015mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room temperature, diatomite mistake Filter, concentrated solvent, saturated aqueous common salt (80mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, it is dense Contracting.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains brown solid 111mg, yield：76.1%.
LC-MS:(pos.ion)m/z:484.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.45 (t, J=5.3Hz, 1H), 8.23 (s, 1H), 7.71 (d, J= 7.6Hz, 1H), 7.64 (d, J=8.0Hz, 1H), 7.55 (dd, J1=13.4Hz, J2=7.6Hz, 1H), 7.35 (d, J= 7.5Hz,1H),6.90–6.67(m,1H),6.18–6.02(m,1H),5.73–5.57(m,1H),4.67–4.56(m,1H), 4.55-4.44 (m, 0.5H), 4.32-4.16 (m, 1H), 4.14 (d, J=5.3Hz, 2H), 4.09-4.02 (m, 0.5H), 3.65- 3.54(m,0.5H),3.13–3.04(m,1H),2.98–2.89(m,0.5H),2.20–2.09(m,1H),2.10–2.02(m, 1H),1.94–1.85(m,1H),1.64–1.49(m,1H).
Embodiment 78
(R)-N- (3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl-s 2- alkynes -1- bases) cyclopropyl-sulfonylamide
Step 1：The synthesis of compound N-(propyl- 2- alkynes -1- bases) cyclopropyl-sulfonylamide
Propargylamine (200mg, 3.63mmol) and TEA (0.56mL, 3.99mmol) are dissolved in dichloromethane (25mL). Cyclopropyl sulfonyl chloride (0.41mL, 3.99mmol) is slowly added under condition of ice bath, is warmed to room temperature, is reacted at room temperature 1 hour.Stopping is stirred Mix, add water (80mL) and be quenched, dichloromethane extraction (50mL × 3).Organic phase is collected, anhydrous sodium sulfate drying, is filtered, it is dense Contracting.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=15/1), obtains weak yellow liquid 420mg, yield：72.6%.
LC-MS:(pos.ion)m/z:160.0[M+1]+.
Step 2：((1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] are phonetic by 3- by compound (R)-N- Pyridine -3- bases) propyl- 2- alkynes -1- bases) cyclopropyl-sulfonylamide synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (150mg, 0.38mmol) is dissolved in DMF (15mL), continuously add N- (propyl- 2- alkynes -1- bases) cyclopropyl-sulfonylamide (110mg, 0.68mmol), cuprous iodide (14mg, 0.075mmol), triethylamine (23mg, 0.23mmol) and tetrakis triphenylphosphine palladium (21mg,0.019mmol).Under nitrogen protection, 80 DEG C of reaction 15h being heated to, stop heating, are cooled to room temperature, diatomite filters, Concentrated solvent, saturated aqueous common salt (80mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration. Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains brown solid 30mg, yield：18.5%.
LC-MS:(pos.ion)m/z:430.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.25 (s, 1H), 7.79 (t, J=5.7Hz, 1H), 6.85-6.68 (m,1H),6.14–6.04(m,1H),5.73–5.58(m,1H),4.70–4.57(m,1H),4.53–4.47(m,0.5H),4.20 (d, J=5.7Hz, 2H), 4.18-4.07 (m, 1H), 4.06-4.00 (m, 0.5H), 3.65-3.58 (m, 0.5H), 3.22-3.14 (m,1H),3.00–2.93(m,0.5H),2.23–2.13(m,1H),2.12–2.04(m,1H),1.95–1.85(m,1H), 1.62–1.53(m,1H),1.01–0.99(m,1H),0.99–0.95(m,2H),0.89–0.76(m,2H).
Embodiment 79
(R)-N- (3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl-s 2- alkynes -1- bases) -4- methoxybenzenesulphoismides
Step 1：The synthesis of compound 4- methoxyl groups-N- (propyl- 2- alkynes -1- bases) benzsulfamide
Propargylamine (200mg, 3.63mmol), TEA (0.56mL, 3.99mmol) and DMAP (5mg, 0.04mmol) are dissolved In dichloromethane (25mL).It is slowly added to, to Methoxybenzenesulfonyl chloride (825mg, 3.99mmol), rise to room under condition of ice bath Temperature, react at room temperature 8 hours.Stop stirring, add water (80mL) and be quenched, dichloromethane extraction (50mL × 3).Collect organic phase, Anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=6/1), obtains pale yellow colored solid Body 632mg, yield：77.27%.
LC-MS:(pos.ion)m/z:226.0[M+1]+.
Step 2：((1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] are phonetic by 3- by compound (R)-N- Pyridine -3- bases) propyl- 2- alkynes -1- bases) -4- methoxybenzenesulphoismides synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (150mg, 0.38mmol) is dissolved in DMF (15mL), continuously adds 4- methoxyl groups-N- (propyl- 2- alkynes -1- bases) benzsulfamide (152mg, 0.68mmol), cuprous iodide (14mg, 0.075mmol), triethylamine (23mg, 0.23mmol) and four (triphenylphosphines) Palladium (21mg, 0.019mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room temperature, diatomite mistake Filter, concentrated solvent, saturated aqueous common salt (80mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, it is dense Contracting.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=45/1), obtains brown solid 118mg, yield：63.2%.
LC-MS:(pos.ion)m/z:496.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.23 (s, 1H), 8.10 (t, J=5.2Hz, 1H), 7.77 (d, J= 8.7Hz,2H),7.02–6.92(m,2H),6.88–6.64(m,1H),6.19–6.02(m,1H),5.74–5.57(m,1H), 4.74–4.55(m,1H),4.55–4.46(m,0.5H),4.34–4.11(m,1H),4.10–4.05(m,0.5H),4.03(d,J =5.7Hz, 2H), 3.60 (d, J=9.8Hz, 3H), 3.58-3.54 (m, 0.5H), 3.13-3.03 (m, 1H), 2.97-2.85 (m,0.5H),2.20–2.09(m,1H),2.09–2.02(m,1H),1.94–1.83(m,1H),1.63–1.50(m,1H).
Embodiment 80
(R)-N- (3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl-s 2- alkynes -1- bases) -3- (trifluoromethyl) benzsulfamide
Step 1：The synthesis of compound N-(propyl- 2- alkynes -1- bases) -3- (trifluoromethyl) benzsulfamide
Propargylamine (200mg, 3.63mmol), TEA (0.56mL, 3.99mmol) and DMAP (5mg, 0.04mmol) are dissolved In dichloromethane (25mL).3- trifluoromethyls benzene sulfonyl chloride (0.64mL, 3.99mmol) is slowly added under condition of ice bath, is risen to Room temperature, react at room temperature 4 hours.Stop stirring, add water (80mL) and be quenched, dichloromethane extraction (50mL × 3).Collect organic Phase, anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=12/1), is obtained yellowish Color liquid 420mg, yield：72.6%.
LC-MS:(pos.ion)m/z:264.0[M+1]+.
Step 2：((1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] are phonetic by 3- by compound (R)-N- Pyridine -3- bases) propyl- 2- alkynes -1- bases) -3- (trifluoromethyl) benzsulfamide synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.30mmol) is dissolved in DMF (15mL), continuously adds N- (propyl- 2- alkynes -1- bases) -3- (trifluoromethyl) benzene sulfonyl Amine (120mg, 0.45mmol), cuprous iodide (11mg, 0.060mmol), triethylamine (18mg, 0.18mmol) and four (triphenyls Phosphine) palladium (18mg, 0.015mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room temperature, diatomite Filtering, concentrated solvent, saturated aqueous common salt (80mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, Concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains brown solid 115mg, yield：71.53%.
LC-MS:(pos.ion)m/z:534.1[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.56 (s, 1H), 8.21 (s, 1H), 8.17 (d, J=7.5Hz, 1H), 8.11 (s, 1H), 7.85 (s, 1H), 7.76 (d, J=7.1Hz, 1H), 6.88-6.66 (m, 1H), 6.17-6.02 (m, 1H),5.74–5.58(m,1H),4.66–4.54(m,1H),4.52–4.45(m,0.5H),4.30–4.19(m,1H),4.18(d, J=4.4Hz, 2H), 4.08-4.01 (m, 0.5H), 3.63-3.52 (m, 0.5H), 3.15-3.08 (m, 1H), 3.07-3.00 (m, 0.5H),2.16–2.08(m,1H),2.07–2.01(m,1H),1.94–1.81(m,1H),1.64–1.52(m,1H).
Embodiment 81
(R)-N- (3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl-s 2- alkynes -1- bases) -2- methyl benzenesulfonamides
Step 1：The synthesis of compound 2- methyl-N- (propyl- 2- alkynes -1- bases) benzsulfamide
Propargylamine (200mg, 3.63mmol), TEA (0.56mL, 3.99mmol) and DMAP (5mg, 0.04mmol) are dissolved In dichloromethane (45mL).2- toluene sulfonyl chlorides (760mg, 3.99mmol) are slowly added under condition of ice bath, are warmed to room temperature, Room temperature reaction 8 hours.Stop stirring, add water (80mL) and be quenched, dichloromethane extraction (50mL × 3).Organic phase is collected, it is anhydrous Sodium sulphate is dried, and is filtered, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=12/1), obtains white solid 640mg, yield：84.2%.
LC-MS:(pos.ion)m/z:210.1[M+1]+.
Step 2：((1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] are phonetic by 3- by compound (R)-N- Pyridine -3- bases) propyl- 2- alkynes -1- bases) -2- methyl benzenesulfonamides synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (130mg, 0.33mmol) is dissolved in DMF (15mL), continuously adds 2- methyl-N- (propyl- 2- alkynes -1- bases) benzsulfamide (105mg, 0.49mmol), cuprous iodide (12mg, 0.065mmol), triethylamine (20mg, 0.20mmol) and four (triphenylphosphines) Palladium (18mg, 0.016mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room temperature, diatomite mistake Filter, concentrated solvent, saturated aqueous common salt (80mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, it is dense Contracting.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains faint yellow solid 130mg, yield：83.03%.
LC-MS:(pos.ion)m/z:480.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.30 (t, J=5.4Hz, 1H), 8.23 (s, 1H), 7.89 (d, J= 7.7Hz,1H),7.45–7.37(m,1H),7.37–7.27(m,2H),6.90–6.65(m,1H),6.17–6.02(m,1H), 5.74–5.57(m,1H),4.68–4.55(m,1H),4.54–4.46(m,0.5H),4.26–4.12(m,1H),4.11–4.06 (m, 0.5H), 4.05 (d, J=5.5Hz, 2H), 3.66-3.57 (m, 0.5H), 3.13-3.07 (m, 1H), 3.00-2.92 (m, 0.5H),2.60(s,3H),2.21–2.10(m,1H),2.10–2.02(m,1H),1.94–1.85(m,1H),1.62–1.51(m, 1H).
Embodiment 82
(R)-N- (3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl-s 2- alkynes -1- bases)-[1,1'- xenyls] -4- sulfonamide
Step 1：The synthesis of compound N-(propyl- 2- alkynes -1- bases)-[1,1'- xenyls] -4- sulfonamide
Propargylamine (120mg, 2.18mmol), TEA (0.33mL, 2.40mmol) and DMAP (2mg, 0.02mmol) are dissolved In dichloromethane (25mL).Distich benzene sulfonyl chloride (605mg, 2.40mmol) is slowly added under condition of ice bath, is warmed to room temperature, room Temperature reaction 8 hours.Stop stirring, add water (80mL) and be quenched, dichloromethane extraction (50mL × 3).Collect organic phase, anhydrous sulphur Sour sodium is dried, and is filtered, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=10/1), obtains white solid 490mg, Yield：82.9%.
LC-MS:(pos.ion)m/z:272.1[M+1]+.
Step 2：((1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] are phonetic by 3- by compound (R)-N- Pyridine -3- bases) propyl- 2- alkynes -1- bases)-[1,1'- xenyls] -4- sulfonamide synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (100mg, 0.25mmol) is dissolved in DMF (15mL), continuously adds N- (propyl- 2- alkynes -1- bases)-[1,1'- xenyl] -4- sulphurs Acid amides (105mg, 0.38mmol), cuprous iodide (10mg, 0.050mmol), triethylamine (15mg, 0.15mmol) and four (triphens Base phosphine) palladium (15mg, 0.013mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room temperature, diatom Soil filtering, concentrated solvent, add saturated aqueous common salt (80mL), dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, mistake Filter, concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains brown solid 115mg, yield： 84.5%.
LC-MS:(pos.ion)m/z:542.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.30 (s, 1H), 8.19 (d, J=32.7Hz, 1H), 7.93 (d, J =7.6Hz, 2H), 7.78-7.65 (m, 2H), 7.45-7.28 (m, 5H), 6.84-6.52 (m, 1H), 6.18-6.03 (m, 1H), 5.73–5.58(m,1H),4.49–4.43(m,1H),4.42–4.38(m,0.5H),4.28–4.18(m,0.5H),4.13(d,J =4.7Hz, 2H), 4.07-3.96 (m, 1H), 3.92-3.83 (m, 0.5H), 3.15-3.07 (m, 1H), 2.99-2.91 (m, 0.5H),2.01–1.90(m,1H),1.84–1.72(m,2H),1.53–1.39(m,1H).
Embodiment 83
(R)-N- (3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl-s 2- alkynes -1- bases) -4- phenoxyphenylsulfonyhalides amine
Step 1：The synthesis of compound 4- phenoxy groups-N- (propyl- 2- alkynes -1- bases) benzsulfamide
Propargylamine (120mg, 2.18mmol), TEA (0.33mL, 2.40mmol) and DMAP (2mg, 0.02mmol) are dissolved In dichloromethane (25mL).4- phenoxyphenylsulfonyhalides chlorine (643mg, 2.40mmol) is slowly added under condition of ice bath, rises to room Temperature, react at room temperature 8 hours.Stop stirring, add water (80mL) and be quenched, dichloromethane extraction (50mL × 3).Collect organic phase, Anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=10/1), obtains pale yellow colored solid Body 300mg, yield：47.9%.
LC-MS:(pos.ion)m/z:288.1[M+1]+.
Step 2：((1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] are phonetic by 3- by compound (R)-N- Pyridine -3- bases) propyl- 2- alkynes -1- bases) -4- phenoxyphenylsulfonyhalides amine synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (100mg, 0.25mmol) is dissolved in DMF (15mL), continuously adds 4- phenoxy groups-N- (propyl- 2- alkynes -1- bases) benzsulfamide (110mg, 0.38mmol), cuprous iodide (10mg, 0.050mmol), triethylamine (15mg, 0.15mmol) and four (triphenylphosphines) Palladium (15mg, 0.013mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room temperature, diatomite mistake Filter, concentrated solvent, saturated aqueous common salt (80mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, it is dense Contracting.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains oily yellow solid 121mg, yield：86.4%.
LC-MS:(pos.ion)m/z:558.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.24 (s, 1H), 8.24-8.17 (m, 1H), 7.84 (d, J= 8.4Hz, 2H), 7.37-7.27 (m, 2H), 7.19 (t, J=7.1Hz, 1H), 7.04-6.93 (m, 2H), 6.81 (d, J= 7.4Hz,2H),6.61–6.44(m,1H),6.16–6.01(m,1H),5.72–5.54(m,1H),4.72–4.57(m,1H), 4.56-4.49 (m, 0.5H), 4.30-4.12 (m, 1H), 4.10 (d, J=5.3Hz, 2H), 4.06-4.01 (m, 0.5H), 3.60- 3.52(m,0.5H),3.12–3.09(m,1H),2.90–2.81(m,0.5H),2.20–2.10(m,1H),2.06–1.98(m, 1H),1.90–1.80(m,1H),1.62–1.49(m,1H).
Embodiment 84
(R) -1- (3- (4- amino -3- (3- (piperidin-1-yl) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine - 1- yls) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 1- (propyl- 2- alkynes -1- bases) piperidines
3- propargyl bromides (1.0g, 8.41mmol) are dissolved in THF (40mL), then add piperidines (0.8mL, 9.25mmol) and Anhydrous potassium carbonate (2.4g, 16.81mmol).Nitrogen is protected, and is heated to 70 DEG C, is reacted 12 hours.Stop adding Heat, it is cooled to room temperature.Add water (80mL), dichloromethane extraction (50mL × 3).Collect organic phase, anhydrous sodium sulfate drying, mistake Filter, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=8/1), obtains oily yellow liquid 227mg, yield： 21.9%.
LC-MS:(pos.ion)m/z:124.1[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- (piperidin-1-yl) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (110mg, 0.28mmol) is dissolved in DMF (15mL), continuously add 1- (propyl- 2- alkynes -1- bases) piperidines (51mg, 0.42mmol), cuprous iodide (10mg, 0.050mmol), triethylamine (17mg, 0.17mmol) and tetrakis triphenylphosphine palladium (15mg,0.013mmol).Under nitrogen protection, 80 DEG C of reaction 15h being heated to, stop heating, are cooled to room temperature, diatomite filters, Concentrated solvent, saturated aqueous common salt (80mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration. Silica gel column chromatography separating purification (DCM/MeOH (v/v)=35/1), obtains brown solid 75mg, yield：69%.
LC-MS:(pos.ion)m/z:394.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.24(s,1H),6.91–6.67(m,1H),6.16–6.05(m, 1H),5.74–5.57(m,1H),4.79–4.57(m,1H),4.57–4.47(m,0.5H),4.32–4.13(m,1H),4.11– 4.02(m,0.5H),3.66(s,2H),3.62–3.57(m,0.5H),3.19–3.12(m,1H),2.97–2.89(m,0.5H), 2.70–2.51(m,4H),2.25–2.14(m,1H),2.11–2.04(m,1H),1.95–1.83(m,1H),1.62–1.57(m, 1H),1.57–1.47(m,4H),1.44–1.34(m,2H).
Embodiment 85
(R) -1- (3- (4- amino -3- (3- morpholine propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperazines Pyridine -1- bases) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 4- (propyl- 2- alkynes -1- bases) morpholine
3- propargyl bromides (1.0g, 0.725mmol) are dissolved in THF (40mL), then add morpholine (0.8mL, 9.0mmol) and Anhydrous potassium carbonate (2.4g, 17mmol).Nitrogen is protected, and is heated to 70 DEG C, is reacted 12 hours.Stop heating, it is cold But to room temperature.Add water (80mL), dichloromethane extraction (50mL × 3).Organic phase is collected, anhydrous sodium sulfate drying, is filtered, it is dense Contracting.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=8/1), obtains oily yellow liquid 392mg, yield：37.2%.
LC-MS:(pos.ion)m/z:126.1[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (3- morpholine propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4-d] Pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (110mg, 0.28mmol) is dissolved in DMF (15mL), continuously add 4- (propyl- 2- alkynes -1- bases) morpholine (51mg, 0.42mmol), cuprous iodide (10mg, 0.050mmol), triethylamine (17mg, 0.17mmol) and tetrakis triphenylphosphine palladium (15mg,0.013mmol).Under nitrogen protection, 80 DEG C of reaction 15h being heated to, stop heating, are cooled to room temperature, diatomite filters, Concentrated solvent, saturated aqueous common salt (80mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration. Silica gel column chromatography separating purification (DCM/MeOH (v/v)=38/1), obtains brown solid 95mg, yield：86.9%.
LC-MS:(pos.ion)m/z:396.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.24(s,1H),6.88–6.68(m,1H),6.17–6.04(m, 1H),5.73–5.58(m,1H),4.78–4.58(m,1H),4.55–4.45(m,0.5H),4.32–4.15(m,1H),4.10– 4.03(m,0.5H),3.80–3.73(m,0.5H),3.66(s,2H),3.64–3.57(m,4H),3.16–3.09(m,1H), 2.96–2.88(m,0.5H),2.64–2.51(m,4H),2.25–2.15(m,1H),2.12–2.03(m,1H),1.93–1.84 (m,1H),1.61–1.51(m,1H).
Embodiment 86
(R) -2- (3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl-s 2- alkynes -1- bases) isoindoline -1,3- diketone
Step 1：The synthesis of compound 2- (propyl- 2- alkynes -1- bases) isoindoline -1,3- diketone
Phthalimide (1g, 6.80mmol) is dissolved in acetone (50mL).Then 3- propargyl bromides are added (0.7mL, 8.16mmol) and potassium carbonate (2.85g, 20.39mmol).Nitrogen is replaced, under nitrogen protection, is heated to 60 DEG C of reactions 12 hours.Stop heating, filter, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=4/1), obtains milky liquid Body 1g, yield：79.45%.
LC-MS:(pos.ion)m/z:186.1[M+1]+.
Step 2：((1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] are phonetic by 3- by compound (R) -2- Pyridine -3- bases) propyl- 2- alkynes -1- bases) isoindoline -1,3- diketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (100mg, 0.25mmol) is dissolved in DMF (15mL), continuously adds 2- (propyl- 2- alkynes -1- bases) isoindoline -1,3- diketone (70mg, 0.38mmol), cuprous iodide (10mg, 0.050mmol), triethylamine (15mg, 0.15mmol) and four (triphenylphosphines) Palladium (15mg, 0.013mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room temperature, diatomite mistake Filter, concentrated solvent, saturated aqueous common salt (80mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, it is dense Contracting.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains brown solid 90mg, yield：78.68%.
LC-MS:(pos.ion)m/z:456.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)8.23(s,1H),8.00–7.78(m,4H),6.84–6.68(m, 1H),6.15–5.98(m,1H),5.75–5.52(m,1H),4.77(s,2H),4.69–4.55(m,1H),4.54–4.44(m, 0.5H),4.30–4.10(m,1H),4.09–3.97(m,0.5H),3.68–3.53(m,0.5H),3.12–3.10(m,1H), 2.97–2.81(m,0.5H),2.23–2.09(m,1H),2.09–1.99(m,1H),1.95–1.80(m,1H),1.62–1.46 (m,1H).
Embodiment 87
(R)-N- (3- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl-s 2- alkynes -1- bases) -5- (dimethylamino) naphthalene -1- sulfonamide
Step 1：The synthesis of compound 5- (dimethylamino)-N- (propyl- 2- alkynes -1- bases) naphthalene -1- sulfonamide
Propargylamine (150mg, 2.72mmol), TEA (0.42mL, 2.99mmol) and DMAP (3mg, 0.03mmol) are dissolved In dichloromethane (25mL).Dansyl chloride (810mg, 2.99mmol) is slowly added under condition of ice bath, is warmed to room temperature, is reacted at room temperature 8 hours.Stop stirring, add water (50mL) and be quenched, dichloromethane extraction (30mL × 3).Organic phase is collected, anhydrous sodium sulfate is done It is dry, filter, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=12/1), obtains weak yellow liquid 670mg, production Rate：85.3%.
LC-MS:(pos.ion)m/z:289.1[M+1]+.
Step 2：((1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] are phonetic by 3- by compound (R)-N- Pyridine -3- bases) propyl- 2- alkynes -1- bases) -5- (dimethylamino) naphthalene -1- sulfonamide synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (100mg, 0.25mmol) is dissolved in DMF (15mL), continuously add 5- (dimethylamino)-N- (propyl- 2- alkynes -1- bases) naphthalene - 1- sulfonamide (110mg, 0.38mmol), cuprous iodide (10mg, 0.050mmol), triethylamine (15mg, 0.15mmol) and four (triphenylphosphine) palladium (15mg, 0.013mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room Temperature, diatomite filtering, concentrated solvent, add saturated aqueous common salt (80mL), dichloromethane extraction (50mL × 3), anhydrous sodium sulfate Dry, filter, concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains brown solid 96mg, yield： 68.4%.
LC-MS:(pos.ion)m/z:559.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.60–8.48(m,1H),8.43–8.30(m,1H),8.26(s, 1H), 8.24-8.09 (m, 2H), 7.67-7.49 (m, 2H), 7.07 (d, J=21.6Hz, 1H), 6.92-6.63 (m, 1H), 6.18–6.01(m,1H),5.74–5.54(m,1H),4.69–4.54(m,1H),4.53–4.45(m,0.5H),4.35–4.16 (m,1H),4.12–4.08(m,0.5H),4.05(s,2H),3.59–3.52(m,0.5H),3.18–3.08(m,1H),2.96– 2.85(m,0.5H),2.63(s,6H),2.17–2.06(m,1H),2.04–1.94(m,1H),1.93–1.82(m,1H),1.63– 1.49(m,1H).
Embodiment 88
(R) -1- (3- (4- amino -3- (the amyl- 1- alkynes -1- bases of 4- hydroxy-4-methyls) -1H- pyrazolos [3,4-d] pyrimidine - 1- yls) piperidin-1-yl) propyl- 2- alkene -1- ketone
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (110mg, 0.28mmol) is dissolved in DMF (15mL), continuously adds the amyl- 4- alkynes -2- alcohol (105mg, 0.38mmol) of 2- methyl, Cuprous iodide (10mg, 0.05mmol), triethylamine (17mg, 0.17mmol) and tetrakis triphenylphosphine palladium (15mg, 0.013mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stop heating, are cooled to room temperature, diatomite filters, and concentration is molten Agent, saturated aqueous common salt (80mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration.Silicagel column Chromatography purifies (DCM/MeOH (v/v)=35/1), obtains oily yellow solid 64mg, yield：62.8%.
LC-MS:(pos.ion)m/z:369.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.22(s,1H),6.85–6.70(m,1H),6.15–6.03(m, 1H),5.74–5.57(m,1H),5.02(s,1H),4.69–4.55(m,1H),4.54–4.47(m,0.5H),4.31–4.14(m, 1H),4.10–4.00(m,0.5H),3.65–3.57(m,0.5H),3.16–3.09(m,1H),2.96–2.87(m,0.5H), 2.63(s,2H),2.23–2.13(m,1H),2.10–2.03(m,1H),1.94–1.83(m,1H),1.62–1.50(m,1H), 1.26(s,6H).
Embodiment 89
(R)-N- (4- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) butyl- 3- alkynes -1- bases) benzsulfamide
Step 1：The synthesis of compound N-(butyl- 3- alkynes -1- bases) benzsulfamide
By butyl- 3- alkynes -1- amine (250mg, 2.17mmol), TEA (0.34mL, 2.40mmol) and DMAP (3mg, 0.03mmol) it is dissolved in dichloromethane (30mL).Benzene sulfonyl chloride (425mg, 2.40mmol) is slowly added under condition of ice bath, is risen To room temperature, react at room temperature 8 hours.Stop stirring, add water (50mL) and be quenched, dichloromethane extraction (50mL × 3).Collect organic Phase, anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=12/1), is obtained yellowish Color liquid 200mg, yield：44.2%.
LC-MS:(pos.ion)m/z:210.1[M+1]+.
Step 2：((1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] are phonetic by 4- by compound (R)-N- Pyridine -3- bases) butyl- 3- alkynes -1- bases) benzsulfamide synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (100mg, 0.25mmol) is dissolved in DMF (15mL), continuously add N- (butyl- 3- alkynes -1- bases) benzsulfamide (80mg, 0.38mmol), cuprous iodide (10mg, 0.050mmol), triethylamine (15mg, 0.15mmol) and tetrakis triphenylphosphine palladium (15mg,0.013mmol).Under nitrogen protection, 80 DEG C of reaction 15h being heated to, stop heating, are cooled to room temperature, diatomite filters, Concentrated solvent, saturated aqueous common salt (80mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration. Silica gel column chromatography separating purification (DCM/MeOH (v/v)=35/1), obtains brown solid 108mg, yield：89%.
LC-MS:(pos.ion)m/z:480.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.23 (s, 1H), 7.98 (t, J=5.6Hz, 1H), 7.83 (d, J= 7.3Hz, 2H), 7.60 (d, J=6.7Hz, 1H), 7.57 (t, J=7.3Hz, 2H), 6.87-6.69 (m, 1H), 6.17-6.04 (m,1H),5.73–5.58(m,1H),4.72–4.56(m,1H),4.55–4.48(m,0.5H),4.34–4.13(m,1H), 4.10–4.04(m,0.5H),3.64–3.56(m,0.5H),3.20–3.12(m,1H),3.12–3.07(m,2H),3.04(dd, J1=12.6Hz, J2=6.4Hz, 2H), 2.93-2.85 (m, 0.5H), 2.23-2.12 (m, 1H), 2.11-2.02 (m, 1H), 1.96–1.84(m,1H),1.63–1.48(m,1H).
Embodiment 90
(R)-N- (4- (1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) butyl- 3- alkynes -1- bases) thiophene -2- sulfonamide
Step 1：The synthesis of compound N-(butyl- 3- alkynes -1- bases) thiophene -2- sulfonamide
By butyl- 3- alkynes -1- amine (200mg, 2.89mmol), TEA (0.45mL, 3.18mmol) and DMAP (3mg, 0.03mmol) it is dissolved in dichloromethane (30mL).Be slowly added under condition of ice bath 2- thiophenesulfonyl chlorides (580mg, 3.18mmol), it is warmed to room temperature, reacts at room temperature 8 hours.Stop stirring, add water (50mL) and be quenched, dichloromethane extraction (50mL ×3).Organic phase is collected, anhydrous sodium sulfate drying, is filtered, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=6/ 1) weak yellow liquid 330mg, yield, are obtained：53.9%.
LC-MS:(pos.ion)m/z:216.0[M+1]+.
Step 2：((1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] are phonetic by 4- by compound (R)-N- Pyridine -3- bases) butyl- 3- alkynes -1- bases) thiophene -2- sulfonamide synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (100mg, 0.25mmol) is dissolved in DMF (15mL), continuously add N- (butyl- 3- alkynes -1- bases) thiophene -2- sulfonamide (80mg, 0.38mmol), cuprous iodide (10mg, 0.050mmol), triethylamine (15mg, 0.15mmol) and tetrakis triphenylphosphine palladium (15mg,0.013mmol).Under nitrogen protection, 80 DEG C of reaction 15h being heated to, stop heating, are cooled to room temperature, diatomite filters, Concentrated solvent, saturated aqueous common salt (50mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration. Silica gel column chromatography separating purification (DCM/MeOH (v/v)=35/1), obtains brown solid 106mg, yield：86.9%.
LC-MS:(pos.ion)m/z:486.1[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.23 (s, 1H), 8.17 (s, 1H), 7.91 (d, J=4.4Hz, 1H), 7.64 (s, 1H), 7.17 (d, J=3.6Hz, 1H), 6.86-6.68 (m, 1H), 6.17-6.02 (m, 1H), 5.73-5.57 (m,1H),4.73–4.56(m,1H),4.55–4.46(m,0.5H),4.34–4.13(m,1H),4.11–4.04(m,0.5H), 3.64–3.56(m,0.5H),3.20–3.13(m,1H),3.12–3.06(m,2H),2.95–2.85(m,0.5H),2.71(t,J =6.5Hz, 2H), 2.23-2.13 (m, 1H), 2.11-2.03 (m, 1H), 1.95-1.83 (m, 1H), 1.64-1.50 (m, 1H)
Embodiment 91
(R, E)-N- (3- (4- amino -1- (1- (4- (dimethylamino) but-2-enes acyl group) piperidines -3- bases) -1H- pyrazoles And [3,4-d] pyrimidin-3-yl) propyl- 2- alkynes -1- bases) benzsulfamide
Step 1：Compound (R, E) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidines -1- Base) -4- (dimethylamino) but-2-ene -1- ketone synthesis
Dimethylamine hydrochloride (45mg, 0.55mmol) is dissolved in DMF (20mL), carbonic acid is then added into reaction solution Potassium (220mg, 1.57mmol), at room temperature stirring reaction 20min.Then by (R, E) -1- (3- (iodo- 1H- pyrazoles of 4- amino -3- And [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -4- bromine but-2-ene -1- ketone (220mg, 0.448mmol) be slowly added into it is above-mentioned In solution.Nitrogen protection is heated to 60 DEG C, reacts 6 hours.Stop heating, be cooled to room temperature, water is added into reaction solution (50mL), ethyl acetate extraction (30mL × 3), anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (DCM/ MeOH (v/v)=10/1), obtain faint yellow solid 166mg, yield：81.3%.
LC-MS:(pos.ion)m/z:456.1[M+1]+.
Step 2：Compound (R, E)-N- (3- (4- amino -1- (1- (4- (dimethylamino) but-2-enes acyl group) piperidines - 3- yls) -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl- 2- alkynes -1- bases) and benzsulfamide synthesis
By (R, E) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) -4- (two Methylamino) but-2-ene -1- ketone (110mg, 0.24mmol) is dissolved in DMF (15mL), continuously add N- (propyl- 2- alkynes -1- bases) benzene Sulfonamide (70mg, 0.36mmol), cuprous iodide (10mg, 0.050mmol), triethylamine (37mg, 0.36mmol) and four (triphens Base phosphine) palladium (15mg, 0.012mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room temperature, diatom Soil filtering, concentrated solvent, add saturated aqueous common salt (50mL), dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, mistake Filter, concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=10/1), obtains brown solid 21mg, yield：16.6%.
LC-MS:(pos.ion)m/z:523.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ (ppm) 8.32 (s, 1H), 8.22 (s, 1H), 7.86 (d, J=3.3Hz, 2H),7.56–7.47(m,3H),6.63(s,1H),6.51–6.38(m,1H),4.70–4.55(m,1H),4.52–4.43(m, 0.5H),4.19–4.08(m,1H),4.06(s,2H),3.71–3.58(m,0.5H),3.22–3.10(m,1H),3.04(s, 2H),2.95–2.86(m,1H),2.15(s,3H),2.13–2.11(m,1H),2.07(s,3H),2.05–1.97(m,1H), 1.93–1.85(m,1H),1.61–1.49(m,1H).
Embodiment 92
(R)-N- (3- (4- amino -1- (1- (butyl- 2- alkynes acyl group) piperidines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -3- Base) propyl- 2- alkynes -1- bases) benzsulfamide
Step 1：Compound (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidines -1- Base) butyl- 2- alkynes -1- ketone synthesis
The iodo- 1- of (R) -3- (piperidines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -4- amine (400mg, 1.16mmol) is molten Solution is in DCM (30mL), then to sequentially adding HATU (530mg, 1.39mmol), triethylamine (353mg, 3.49mmol) and 2- Tetrolic acid (117mg, 1.39mmol).Nitrogen is protected, and reaction 12 hours is stirred at room temperature.After reaction completely, diatomite filtering, concentration Solvent, silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains faint yellow solid product 400mg, yield： 83.9%.
LC-MS:(pos.ion)m/z:411.0[M+1]+.
Step 2：Compound (R)-N- (3- (4- amino -1- (1- (butyl- 2- alkynes acyl group) piperidines -3- bases) -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl- 2- alkynes -1- bases) benzsulfamide synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) butyl- 2- alkynes - 1- ketone (150mg, 0.36mmol) is dissolved in DMF (15mL), continuously add N- (propyl- 2- alkynes -1- bases) benzsulfamide (107mg, 0.55mmol), cuprous iodide (14mg, 0.073mmol), triethylamine (56mg, 0.55mmol) and tetrakis triphenylphosphine palladium (21mg,0.018mmol).Under nitrogen protection, 80 DEG C of reaction 15h being heated to, stop heating, are cooled to room temperature, diatomite filters, Concentrated solvent, saturated aqueous common salt (80mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration. Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains brown solid 79mg, yield：45.2%.
LC-MS:(pos.ion)m/z:478.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.31 (d, J=2.1Hz, 1H), 8.24 (d, J=18.5Hz, 1H), 7.91-7.82 (m, 2H), 7.53 (d, J=1.9Hz, 1H), 7.52 (d, J=3.4Hz, 2H), 4.73-4.55 (m, 1H), 4.39- 4.29 (m, 0.5H), 4.27-4.17 (m, 1H), 4.07 (d, J=4.1Hz, 2H), 4.00-3.93 (m, 0.5H), 3.84-3.73 (m,0.5H),3.32–3.22(m,1H),3.21–3.14(m,0.5H),3.11–3.06(m,1H),2.20–2.13(m,1H), 2.05(s,2H),1.97–1.91(m,1H),1.84(s,1H),1.67–1.52(m,1H).
Embodiment 93
N- (3- (1- (1- acryloyl azetidin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl-s 2- alkynes -1- bases) benzsulfamide
Step 1：The synthesis of compound tert-butyl group 3- ((methyl sulphonyl) epoxide) azetidine -1- carboxylates
Tert-butyl group 3- hydroxy azetidine -1- carboxylates (2g, 11.55mmol) are dissolved in dichloromethane (80mL) In, triethylamine (2.1mL, 15mmol) is then added into reaction solution, mesyl chloride (1.1mL, 14mmol) is added under ice-water bath With DMAP (145mg, 1.16mmol).It is stirred at room temperature 12 hours, dichloromethane extraction (60mL × 3), saturation food Salt washes (60mL × 3), anhydrous sodium sulfate drying, removes solvent, silica gel column chromatography separating purification (PE/EtOAc (v/v) under reduced pressure =2/1) weak yellow liquid 2.8g, yield, are obtained：96%.
LC-MS:(pos.ion)m/z:252.1[M+1]+.
Step 2：Compound tert-butyl group 3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) azetidin The synthesis of alkane -1- carboxylates
Iodo- 1H- pyrazolos [3, the 4-d] pyrimidine -4- amine (2g, 7.66mmol) of 3- are dissolved in DMF (100mL), then The tert-butyl group 3- ((methyl sulphonyl) epoxide) azetidine -1- carboxylates (2.9g, 12mmol), carbonic acid are added into reaction solution Caesium (6.3g, 19mmol) and DMAP (480mg, 3.85mmol).Stirred 12 hours at 90 DEG C.Stop heating, it is cold But to room temperature, filtering, DMF, dichloromethane extraction (70mL × 3), saturated common salt washing (60mL × 3), anhydrous sulphur are removed under reduced pressure Sour sodium is dried, and is removed solvent under reduced pressure, silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), is obtained faint yellow solid Product 2g, yield：61.2%.
LC-MS:(pos.ion)m/z:417.0[M+1]+.
Step 3：The synthesis of iodo- 1H- pyrazolos [3,4-d] pyrimidine -4- amine of compound 1- (azetidin -3- bases) -3-
By tert-butyl group 3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) azetidine -1- carboxylates (2g, 4.80mmol) is dissolved in dioxane (60mL), and hydrochloric acid (4M, 60mL) is then added into reaction solution.It is stirred at room temperature 16 hours, after having reacted, dilute sodium hydrate aqueous solution is added, is adjusted to pH=9, dichloromethane extraction (60mL × 3), saturation food Salt washes (60mL × 3), anhydrous sodium sulfate drying, removes solvent, silica gel column chromatography separating purification (DCM/MeOH (v/v) under reduced pressure =6/1) white solid product 450mg, yield, are obtained：29.6%.LC-MS:(pos.ion)m/z:317.0[M+1]+.
Step 4：Compound 1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) azetidin -1- Base) propyl- 2- alkene -1- ketone synthesis
Iodo- 1H- pyrazolos [3,4-d] pyrimidine -4- amine (300mg, 0.95mmol) of 1- (azetidin -3- bases) -3- is molten In dichloromethane (40mL), triethylamine (146mg, 1.42mmol) is added.Be slowly added at 0 DEG C acryloyl chloride (105mg, 1.14mmol), reaction 20min is stirred at room temperature.After reaction completely, saturated aqueous common salt (50mL), dichloromethane extraction (30mL are added × 3), organic phase anhydrous sodium sulfate drying, concentration, silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), is obtained white Color product 217mg, yield：61.7%.
LC-MS:(pos.ion)m/z:371.0[M+1]+.
Step 5：Compound N-((1- (1- acryloyl azetidin -3- bases) -4- amino -1H- pyrazolos [3,4-d] are phonetic by 3- Pyridine -3- bases) propyl- 2- alkynes -1- bases) benzsulfamide synthesis
By 1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) azetidin -1- bases) propyl- 2- alkene - 1- ketone (130mg, 0.35mmol) is dissolved in DMF (15mL), continuously add N- (propyl- 2- alkynes -1- bases) benzsulfamide (105mg, 0.54mmol), cuprous iodide (14mg, 0.074mmol), triethylamine (54mg, 0.53mmol) and tetrakis triphenylphosphine palladium (21mg,0.018mmol).Under nitrogen protection, 80 DEG C of reaction 15h being heated to, stop heating, are cooled to room temperature, diatomite filters, Concentrated solvent, saturated aqueous common salt (50mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration. Silica gel column chromatography separating purification (DCM/MeOH (v/v)=35/1), obtains sepia solid 118mg, yield：76.8%.
LC-MS:(pos.ion)m/z:438.1[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)8.31(s,1H),8.23(s,1H),7.86(s,2H),7.52(s, 3H),6.68–6.47(m,1H),6.39(dd,J1=16.8Hz, J2=10.4Hz, 1H), 6.22-6.11 (m, 1H), 5.73 (d, J =10.0Hz, 1H), 5.70-5.60 (m, 1H), 4.77-4.67 (m, 1H), 4.56-4.47 (m, 1H), 4.48-4.38 (m, 1H), 4.28–4.19(m,1H),4.14–4.00(m,2H).
Embodiment 94
(R)-N- (3- (4- amino -1- (1- (butyl- 2- alkynes acyl group) pyrrolidin-3-yl) -1H- pyrazolos [3,4-d] pyrimidine - 3- yls) propyl- 2- alkynes -1- bases) benzsulfamide
Step 1：The synthesis of compound (S)-tert-butyl group 3- ((methyl sulphonyl) epoxide) pyrrolidines -1- carboxylates
(S)-tert-butyl group 3- hydroxyl pyrrolidine -1- carboxylates (1g, 5.34mmol) are dissolved in dichloromethane (50mL), Then triethylamine (1mL, 6.94mmol) is added into reaction solution, add under ice-water bath mesyl chloride (0.5mL, 6.41mmol) and DMAP (66mg, 1.53mmol).It is stirred at room temperature 12 hours, dichloromethane extraction (50mL × 3), saturated aqueous common salt Wash (50mL × 3), anhydrous sodium sulfate drying, remove solvent, silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/ under reduced pressure V)=2/1), weak yellow liquid 662mg, yield are obtained：46.7%.LC-MS (pos.ion) m/z:266.1[M+1]+.
Step 2：Compound (R)-tert-butyl group 3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) pyrroles The synthesis of alkane -1- carboxylates
Iodo- 1H- pyrazolos [3, the 4-d] pyrimidine -4- amine (600mg, 2.30mmol) of 3- are dissolved in DMF (50mL), so Added in backward reaction solution (S)-tert-butyl group 3- ((methyl sulphonyl) epoxide) pyrrolidines -1- carboxylates (920mg, 3.47mmol), cesium carbonate (1.9g, 5.8mmol) and DMAP (145mg, 1.16mmol).Stirring 8 is small at 90 DEG C When, after having reacted, remove DMF, dichloromethane extraction (50mL × 3), saturated common salt washing (60mL × 3), anhydrous slufuric acid under reduced pressure Sodium is dried, and is removed solvent under reduced pressure, silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), is obtained faint yellow solid production Thing 657mg, yield：66.4%.
LC-MS(pos.ion)m/z:431.1[M+1]+.
Step 3：Compound (R)-tert-butyl group 3- (4- amino -3- (3- (phenylSulphon amido) propyl- 1- alkynes -1- bases) -1H- Pyrazolo [3,4-d] pyrimidine -1- bases) pyrrolidines -1- carboxylates synthesis
By (R)-tert-butyl group 3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) pyrrolidines -1- carboxylates (440mg, 1.02mmol) is dissolved in DMF (30mL), continuously add N- (propyl- 2- alkynes -1- bases) benzsulfamide (300mg, 1.54mmol), cuprous iodide (40mg, 0.21mmol), triethylamine (62mg, 0.61mmol) and tetrakis triphenylphosphine palladium (60mg, 0.052mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stop heating, are cooled to room temperature, diatomite filters, and concentration is molten Agent, saturated aqueous common salt (60mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration.Silicagel column Chromatography purifies (DCM/MeOH (v/v)=35/1), obtains brown solid 492mg, yield：96.6%.
LC-MS(pos.ion)m/z:498.2[M+1]+.
Step 4：Compound (R)-N- (3- (4- amino -1- (pyrrolidin-3-yl) -1H- pyrazolo [3,4-d] pyrimidines -3- Base) propyl- 2- alkynes -1- bases) benzsulfamide synthesis
By (R)-tert-butyl group 3- (4- amino -3- (3- (phenylSulphon amido) propyl- 1- alkynes -1- bases) -1H- pyrazolos [3,4- D] pyrimidine -1- bases) pyrrolidines -1- carboxylates (492mg, 0.99mmol) are dissolved in dioxane (15mL), then to reaction Hydrochloric acid (4M, 15mL) is added in liquid.It is stirred at room temperature 16 hours, after reaction completely, adds dilute sodium hydrate aqueous solution, be adjusted to pH =9, dichloromethane extraction (50mL × 3), saturated common salt washing (50mL × 3), anhydrous sodium sulfate drying, remove solvent under reduced pressure, Silica gel column chromatography separating purification (DCM/MeOH (v/v)=6/1), obtains faint yellow solid product 250mg, yield：63.6%.
LC-MS(pos.ion)m/z:398.1[M+1]+.
Step 5：Compound (R)-N- (3- (4- amino -1- (1- (butyl- 2- alkynes acyl group) pyrrolidin-3-yl) -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl- 2- alkynes -1- bases) benzsulfamide synthesis
By (R)-N- (3- (4- amino -1- (pyrrolidin-3-yl) -1H- pyrazolos [3,4-d] pyrimidin-3-yl) propyl- 2- alkynes - 1- yls) benzsulfamide (120mg, 0.30mmol) is dissolved in DCM (30mL), then to sequentially add HATU (140mg, 0.37mmol), triethylamine (91mg, 0.92mmol) and 2- tetrolic acid (31mg, 0.37mmol).Nitrogen is protected, and is stirred at room temperature anti- Answer 12 hours.After reaction completely, diatomite filtering, concentrated solvent, silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/ 1) brown solid 29mg, yield, are obtained：20.7%.
LC-MS:(pos.ion)m/z:464.1[M+1]+；
1H NMR(400MHz,DMSO-d6):δ (ppm) 8.29 (t, J=5.6Hz, 1H), 8.23 (d, J=4.1Hz, 1H), 7.90-7.81 (m, 2H), 7.56-7.47 (m, 3H), 4.07 (d, J=5.6Hz, 2H), 3.93-3.86 (m, 0.5H), 3.82- 3.78 (m, 1H), 3.70-3.64 (m, 0.5H), 3.59-3.51 (m, 1H), 3.10 (q, J=7.3Hz, 2H), 2.45-2.36 (m, 1H), 2.31-2.21 (m, 1H), 2.02 (d, J=26.3Hz, 3H)
Embodiment 95
(R) -1- (3- (4- amino -3- ((3- (benzyloxy) phenyl) acetenyl) -1H- pyrazolos [3,4-d] pyrimidine -1- Base) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 3- ((trimethyl silicon substrate) acetenyl) phenol
3- iodophenols (3.5g, 16mmol) are dissolved in THF (120mL), cuprous iodide is then added into reaction solution (180mg, 0.95mmol), bi triphenyl phosphorus palladium chloride (330mg, 0.48mmol), diethylamine (25mL, 240mmol) and three Allylene silicon (2.7mL, 19mmol).Under nitrogen protection, reaction 24h is stirred at room temperature.Stop heating, cooling, into reaction solution Water (200mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration, silica gel column chromatography separates pure Change (PE/EtOAc (v/v)=15/1), obtain dark brown liquid 2.7g, yield：89%.
LC-MS:(pos.ion)m/z:191.08[M+1]+.
Step 2：The synthesis of compound 3- acetenyl phenol
3- ((trimethyl silicon substrate) acetenyl) phenol (1.3g, 6.8mmol) is dissolved in methanol (20mL) and THF (20mL) In the mixed solvent, potassium hydroxide (0.46g, 8.2mmol) is added in reaction solution.Replace nitrogen three times, under nitrogen protection, room temperature Stirring reaction 10h.Stop reaction, concentrate, addition water (100mL), hydrochloric acid (4N) regulation pH to 6, dichloromethane extraction (50mL × 3).Anhydrous sodium sulfate drying, filter, concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=15/1), obtain yellowish Color grease 710mg, yield：88%.
LC-MS(pos.ion)m/z:119.05[M+1]+.
Step 3：The synthesis of compound 1- (benzyloxy) -3- acetylenylbenzenes
3- acetenyls phenol (710mg, 6.01mmol) is dissolved in DMF (30mL), then adds Anhydrous potassium carbonate (1.65g, 12.02mmol) and benzyl chloride (1mL, 9.01mmol, 1.1g/mL), heating reflux reaction 6h.Stop reaction, to reaction In liquid plus water (100mL), addition watery hydrochloric acid regulation pH to 1, ethyl acetate extract three times (150mL).Merge organic phase, anhydrous sulphur Sour sodium is dried, and concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=90/1), obtains weak yellow liquid 420mg, is produced Rate：42.3%.
LC-MS:(pos.ion)m/z:209.09[M+1]+.
Step 4：The synthesis of iodo- 1H- pyrazolos [3,4-d] pyrimidine -4- amine of compound 3-
1H- pyrazolos [3,4-d] pyrimidine -4- amine (18.0g, 130.54mmol) is dissolved in DMF (150mL), then N- N-iodosuccinimides (45g, 195.81mmol, Aldrich) are slowly added into reaction solution, stirring reaction 12 is small at 80 DEG C When.Stop heating, cooling, water (200mL) is added into reaction solution, filter, wash (80mL), ethanol (60mL) is washed, and is dried, is obtained To gray solid 25.8g, yield：75.7%.LC-MS:(pos.ion)m/z:261.9[M+1]+.
Step 5：The synthesis of compound (S)-tert-butyl group 3- ((mesyl) epoxide) piperidines -1- carboxylates
(S)-tert-butyl group 3- hydroxy piperidine -1- carboxylates (20.0g, 97.1mmol) are dissolved in dichloromethane (200mL) In, triethylamine (18mL, 126mmol) is then added into reaction solution, mesyl chloride (8.3mL, 107mmol) is added under ice-water bath With DMAP (1.21g, 9.71mmol).It is stirred at room temperature 12 hours, dichloromethane (150mL) extraction, saturated common salt Wash (60mL), anhydrous sodium sulfate drying, remove solvent, silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/ under reduced pressure V)=6/1), white solid 21g, yield 77.4% are obtained.
LC-MS(pos.ion)m/z:224.1(M-55).
Step 6：Compound (R)-tert-butyl group 3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidines - The synthesis of 1- carboxylates
Iodo- 1H- pyrazolos [3, the 4-d] pyrimidine -4- amine (5.0g, 18.77mmol) of 3- are dissolved in DMF (150mL), so (S)-tert-butyl group 3- ((mesyl) epoxide) piperidines -1- carboxylates (17.5g, 56.4mmol), carbon are added in backward reaction solution Sour caesium (18.5g, 56.2mmol) and DMAP (3.5g, 28mmol).Stir 8 hours at 90 DEG C, after having reacted, subtract DMF is evaporated off in pressure, dichloromethane (150mL) extraction, saturated common salt washing (100mL), anhydrous sodium sulfate drying, removes under reduced pressure molten Agent, silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains product 3.4g, yield：41%.
LC-MS(pos.ion)m/z:445.27[M+1]+.
Step 7：The synthesis of the iodo- 1- of compound (R) -3- (piperidines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -4- amine
By (R)-tert-butyl group 3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidines -1- carboxylates (1.0g, 2.25mmol) is dissolved in dioxane (6mL), and hydrochloric acid (4N, 6mL) is then added into reaction solution, is stirred at room temperature 16 hours, after having reacted, dilute sodium hydrate aqueous solution is added, is adjusted to pH=9, dichloromethane (150mL) extraction, saturated common salt Wash (60mL), anhydrous sodium sulfate drying, remove solvent, silica gel column chromatography separating purification (DCM/MeOH (v/v)=12/ under reduced pressure 1-6/1), product 700mg, yield are obtained：90%.
LC-MS(pos.ion)m/z:345.15[M+1]+.
Step 8：Compound (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidines -1- Base) propyl- 2- alkene -1- ketone synthesis
The iodo- 1- of (R) -3- (piperidines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -4- amine (5g, 14.528mmol) is dissolved in In dichloromethane (250mL), sequentially added at 0 DEG C triethylamine (5.5mL, 36.32mmol) and three chlorpromazine chlorides (3mL, 29.056mmol), reaction 4 hours is stirred at room temperature, is slowly added to DBU (22mL, 145.28mmol), reacts at room temperature 12 hours.Instead After answering completely, saturated aqueous common salt (150mL) is washed three times, organic phase anhydrous sodium sulfate drying, concentration, and silica gel column chromatography separation is pure Change (DCM/MeOH (v/v)=80/1-60/1), obtain faint yellow product 1.2g, yield：21%.
LC-MS:(pos.ion)m/z:399.04[M+1]+.
Step 9：Compound (R) -1- (3- (4- amino -3- ((3- (benzyloxy) phenyl) acetenyl) -1H- pyrazolos [3, 4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (120mg, 0.301mmol) is dissolved in DMF (12mL), continuously add 1- (benzyloxy) -3- acetylenylbenzenes (130mg, 0.602mmol), cuprous iodide (12mg, 0.06mmol), triethylamine (18mg, 0.105mmol) and tetrakis triphenylphosphine palladium (18mg,0.015mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filtering, concentrated solvent, adds saturation Saline solution (100mL), dichloromethane (150mL) extraction.Silica gel thin-layer analysis isolates and purifies (PE/EtOAc (v/v)=15/1), obtains To oily yellow solid 60mg, yield：41.6%.
LC-MS:(pos.ion)m/z:479.22[M+1]+；
1H NMR(400MHz,DMSO-d6):δ (ppm) 8.26 (s, 1H), 7.47 (d, J=7.3Hz, 2H), 7.44-7.37 (m,4H),7.33(dd,J1=17.5Hz, J2=7.3Hz, 2H), 7.13 (d, J=7.0Hz, 1H), 6.91-6.65 (m, 1H), 6.18–6.02(m,1H),5.77–5.55(m,1H),5.17(s,2H),4.78–4.61(m,1H),4.59–4.47(m,0.5H), 4.35–4.15(m,1H),4.11–3.97(m,0.5H),3.74–3.56(m,0.5H),3.22–3.05(m,1H),3.02–2.83 (m,0.5H),2.29–2.16(m,1H),2.15–2.05(m,1H),1.95–1.86(m,1H),1.66–1.49(m,1H).
Embodiment 96
(R) -1- (3- (4- amino -3- ((3- ((2- methylthiazol -5- bases) methoxyl group) phenyl) acetenyl) -1H- pyrazoles And [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound (2- methylthiazol -5- bases) methanol
5- aldehyde radical -2- methylthiazols (1.65g, 12.3mmol) are dissolved in methanol (50mL), 0 DEG C of addition sodium hydride (0.8g, 21.02mmol), continue to react 15min, react 3h at room temperature.After reaction completely, ammonium chloride saturated solution is added (100mL), ethyl acetate (200mL) extraction, merges organic phase, anhydrous sodium sulfate drying；Filtering, concentration, obtains yellow oily Liquid 1.45g, yield：91.7%.
LC-MS:(pos.ion)m/z:130.03[M+1]+.
Step 2：The synthesis of compound 2- methyl -5- ((3- ((trimethyl silicon substrate) acetenyl) phenoxy group) methyl) thiazole
By (2- methylthiazol -5- bases) methanol (820mg, 6.4mmol) and 3- ((trimethyl silicon substrate) acetenyl) phenol (1.1g, 5.8mmol) is dissolved in THF (80mL), then sequentially adds triphenylphosphine (4.5g, 17mmol) and DIAD (3.4mL, 17mmol), under nitrogen protection, reaction 1h is stirred at room temperature.After reaction completely, addition saturated aqueous common salt (100mL), two Chloromethanes (150mL) extracts, and merges organic phase, anhydrous sodium sulfate drying, concentrated solvent.Silica gel column chromatography separating purification (PE/ EtOAc (v/v)=20/1), obtain yellowish-brown liquid 900mg, yield：50%.
LC-MS(ESI,pos.ion)m/z:302.1[M+1]+.
Step 3：The synthesis of compound 5- ((3- acetylenylbenzenes epoxide) methyl) -2- methylthiazols
2- methyl -5- ((3- ((trimethyl silicon substrate) acetenyl) phenoxy group) methyl) thiazole (1.5g, 5mmol) is dissolved in The in the mixed solvent of methanol (20mL) and THF (20mL), potassium hydroxide (0.42g, 7.5mmol) is added in reaction solution.Replace nitrogen Three times, under nitrogen protection, reaction 10h is stirred at room temperature in gas.Stop reaction, concentration, add water (100mL), hydrochloric acid (4N) regulation pH To 6, dichloromethane extracts (50mL × 3).Anhydrous sodium sulfate drying, filter, concentration, silica gel column chromatography separating purification (PE/ EtOAc (v/v)=15/1), obtain pale yellow oil 380mg, yield：33%.
LC-MS(pos.ion)m/z:230.06[M+1]+.
Step 4：Compound (R) -1- (3- (4- amino -3- ((3- ((2- methylthiazol -5- bases) methoxyl group) phenyl) acetylene Base) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (130mg, 0.326mmol) is dissolved in DMF (15mL), continuously adds 5- ((3- acetylenylbenzenes epoxide) methyl) -2- methyl thiazoliums Azoles (150mg, 0.652mmol), cuprous iodide (13mg, 0.065mmol), triethylamine (0.03mL, 0.195mmol) and four (three Phenylphosphine) palladium (19mg, 0.016mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filters, concentration is molten Agent, add saturated aqueous common salt (100mL), dichloromethane (150mL) extraction.Silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v) =30/1) oily yellow solid 38mg, yield, are obtained：23.3%.
LC-MS:(pos.ion)m/z:500.18[M+1]+；
1H NMR(600MHz,CDCl3):δ (ppm) 8.36 (s, 1H), 7.62 (s, 1H), 7.32 (t, J=7.9Hz, 1H), 7.22 (d, J=7.5Hz, 1H), 7.17 (s, 1H), 7.03 (d, J=7.3Hz, 1H), 6.65-6.51 (m, 1H), 6.36-6.24 (m,1H),5.96(s,2H),5.77–5.61(m,1H),4.90–4.79(m,1H),4.71–4.58(m,0.5H),4.32–4.12 (m,1H),4.10–3.99(m,0.5H),3.75–3.64(m,0.5H),3.40–3.20(m,1H),2.85–2.77(m,0.5H), 2.72(s,3H),2.40–2.27(m,1H),2.27–2.18(m,1H),2.02–1.95(m,1H),1.62–1.53(m,1H).
Embodiment 97
(R) -1- (3- (4- amino -3- ((4- (2- methoxy ethoxies) phenyl) acetenyl) -1H- pyrazolos [3,4-d] Pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 4- ((trimethyl silicon substrate) acetenyl) phenol
4- iodophenols (1.5g, 6.8mmol) are dissolved in THF (80mL), cuprous iodide is then added into reaction solution (78mg, 0.41mmol), bi triphenyl phosphorus palladium chloride (140mg, 0.2mmol) and diethylamine (16mL, 160mmol).Nitrogen Under protection, reaction 24h is stirred at room temperature.Stop heating, cooling, water (150mL), dichloromethane extraction are added into reaction solution (50mL × 3), anhydrous sodium sulfate drying, filter, concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=12/1), obtain To weak yellow liquid 1.25g, yield：96%.
LC-MS:(pos.ion)m/z:191.08[M+1]+.
Step 2：The synthesis of compound 4- acetenyl phenol
4- ((trimethyl silicon substrate) acetenyl) phenol (1.2g, 6.3mmol) is dissolved in methanol (15mL) and THF (15mL) In the mixed solvent, potassium hydroxide (1.4g, 25mmol) is added in reaction solution.Replace nitrogen three times, under nitrogen protection, room temperature is stirred Mix reaction 10h.Stop reaction, concentrate, addition water (100mL), hydrochloric acid (4N) regulation pH to 6, dichloromethane extraction (50mL × 3).Anhydrous sodium sulfate drying, filter, concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=12/1), obtain yellowish Color grease 450mg, yield：56%.
LC-MS(pos.ion)m/z:119.05[M+1]+.
Step 3：The synthesis of compound 1- acetenyls -4- (2- methoxy ethoxies) benzene
4- acetenyls phenol (410mg, 3.47mmol) is dissolved in DMF (25mL), then adds Anhydrous potassium carbonate (960mg, 6.94mmol) and 2- Bromoethyl methyl ethers (0.6mL, 6.24mmol, 1.1g/mL), it is heated to 85 DEG C of reaction 12h.Stop Reaction, concentrated solvent, add water (80mL), ethyl acetate extraction (50mL × 3).Merge organic phase, anhydrous sodium sulfate drying is dense Contracting, silica gel column chromatography separating purification (PE/EtOAc (v/v)=20/1), obtains colourless liquid 310mg, yield：50.6%.
LC-MS:(pos.ion)m/z:177.08[M+1]+.
Step 4：Compound (R) -1- (3- (4- amino -3- ((4- (2- methoxy ethoxies) phenyl) acetenyl) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (130mg, 0.326mmol) is dissolved in DMF (15mL), continuously adds 1- acetenyls -4- (2- methoxy ethoxies) benzene (86mg, 0.489mmol), cuprous iodide (12mg, 0.06mmol), triethylamine (18mg, 0.105mmol) and four (triphenylphosphines) Palladium (18mg, 0.015mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filtering, concentrated solvent, adds full With saline solution (100mL), dichloromethane (50mL × 3) extraction.Silica gel thin-layer analysis isolates and purifies (PE/EtOAc (v/v)=1/ 12) oily yellow solid 41mg, yield, are obtained：27.4%.
LC-MS:(pos.ion)m/z:447.21[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.25 (s, 1H), 7.66 (d, J=8.8Hz, 2H), 7.07-6.98 (m,2H),6.87–6.71(m,1H),6.16–6.06(m,1H),5.73–5.60(m,1H),4.73–4.62(m,1H),4.58– 4.52(m,0.5H),4.32–4.18(m,1H),4.18–4.12(m,2H),4.12–4.04(m,0.5H),3.74–3.65(m, 2H),3.64–3.59(m,0.5H),3.31(s,3H),3.28–3.23(m,1H),3.05–3.00(m,0.5H),2.26–2.18 (m,1H),2.14–2.05(m,1H),1.94–1.86(m,1H),1.67–1.60(m,1H).
Embodiment 98
(R) -1- (3- (4- amino -3- ((3- (2- methoxy ethoxies) phenyl) acetenyl) -1H- pyrazolos [3,4-d] Pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 1- acetenyls -3- (2- methoxy ethoxies) benzene
3- acetenyls phenol (300mg, 2.53mmol) is dissolved in DMF (25mL), then adds Anhydrous potassium carbonate (702mg, 5.07mmol) and 2- Bromoethyl methyl ethers (0.44mL, 4.57mmol, 1.1g/mL), it is heated to 85 DEG C of reaction 12h.Stop Only react, concentrated solvent, add water (60mL), ethyl acetate extraction (50mL × 3).Merging organic phase, anhydrous sodium sulfate drying, Concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=24/1), obtains colourless liquid 300mg, yield：67%.
LC-MS:(pos.ion)m/z:177.08[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- ((3- (2- methoxy ethoxies) phenyl) acetenyl) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (100mg, 0.251mmol) is dissolved in DMF (15mL), continuously adds 1- acetenyls -3- (2- methoxy ethoxies) benzene (70mg, 0.376mmol), cuprous iodide (10mg, 0.05mmol), triethylamine (15mg, 0.150mmol) and four (triphenylphosphines) Palladium (15mg, 0.012mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filtering, concentrated solvent, adds full With saline solution (100mL), dichloromethane (50mL × 3) extraction.Silica gel thin-layer analysis isolates and purifies (PE/EtOAc (v/v)=1/ 12) oily yellow solid 51mg, yield, are obtained：44.1%.
LC-MS:(pos.ion)m/z:447.21[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.26(s,1H),7.36(dd,J1=17.1Hz, J2=9.0Hz, 2H), 7.29 (d, J=7.6Hz, 1H), 7.06 (dd, J1=8.3Hz, J2=1.8Hz, 1H), 6.90-6.68 (m, 1H), 6.17- 6.04(m,1H),5.73–5.58(m,1H),4.73–4.60(m,1H),4.60–4.51(m,0.5H),4.31–4.19(m,1H), 4.15(dd,J1=5.3Hz, J2=3.8Hz, 2H), 4.12-4.03 (m, 0.5H), 3.69-3.65 (m, 2H), 3.66-3.60 (m, 0.5H),3.31(s,3H),3.21–3.11(m,1H),2.98–2.88(m,0.5H),2.27–2.17(m,1H),2.15–2.07 (m,1H),1.94–1.86(m,1H),1.64–1.52(m,1H).
Embodiment 99
(R) -3- ((1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) acetylene Base)-N- cyclopropyl-phenyl formamides
Step 1：The synthesis of compound 3- iodo-benzoic acid methyl esters
3- iodo-benzoic acids (2g, 8.063mmol) are dissolved in methanol (45mL), then add the concentrated sulfuric acid (2mL, 36.8mmol), heating reflux reaction 24 hours.Stop reaction, concentrated solvent, add water (180mL), ethyl acetate extraction (80mL×3).Organic phase is collected, anhydrous sodium sulfate drying, is filtered, concentration.Obtain weak yellow liquid 2g, yield：94.65%.
LC-MS:(pos.ion)m/z:262.95[M+1]+.
Step 2：The synthesis of compound 3- ((trimethyl silicon substrate) acetenyl) methyl benzoate
3- iodo-benzoic acids methyl esters (2.0g, 7.63mmol) is dissolved in THF (50mL), then adds cuprous iodide (85mg, 0.44mmol) and bi triphenyl phosphorus palladium chloride (150mg, 0.22mmol).Replace nitrogen three times, under nitrogen protection, It is slowly added to diethylamine (8.3mL, 80mmol) and trimethylsilyl acetylene (1.7mL, 12mmol).Nitrogen is protected, room temperature reaction 24 Hour.After reaction completely, filtering, filtrate is concentrated, add saturated aqueous common salt (60mL), ethyl acetate extraction (60mL × 3), merge Organic phase, anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=60/1), is obtained Oily yellow liquid 1g, yield：78%.
LC-MS(pos.ion)m/z:233.1[M+1]+.
Step 3：The synthesis of compound 3- acetylenylbenzene formic acid
3- ((trimethyl silicon substrate) acetenyl) methyl benzoate (1.6g, 6.9mmol) is dissolved in methanol (40mL), so Sodium hydroxide (0.83g, 20.8mmol) is added afterwards.Under nitrogen protection, reaction 8h is stirred at room temperature.After reaction completely, hydrochloric acid solution (2N) adjusts pH to 5.Concentrated solvent, ethyl acetate extraction (50mL × 3), merge organic phase, anhydrous sodium sulfate drying, concentrate molten Agent.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=6/1), obtains faint yellow solid 717mg, yield：71%.
LC-MS:(pos.ion)m/z:147.0[M+1]+.
Step 4：The synthesis of compound N-cyclopropyl -3- acetylenylbenzene formamides
3- acetylenylbenzenes formic acid (0.4g, 2.73mmol) is dissolved in DMF (30mL), then adds 1- hydroxy benzos three Azoles (HOBT) (1.2g, 8.2mmol) and DIPEA (DIPEA) (1.8mL, 10.9mmol, 0.78g/mL), nitrogen Protection, stirs 3h at room temperature.Cyclopropylamine (0.76mL, 10.9mmol, 0.82g/mL) is slowly added into above-mentioned solution, room temperature Stirring reaction 13h.After reaction completely, concentrated solvent, saturated sodium bicarbonate aqueous solution (100mL), acetic acid second are added into reaction solution Ester extracts (50mL × 3), and organic phase is with saturated common salt water washing (60mL × 3).Anhydrous sodium sulfate drying, concentration, silica gel column layer Analysis isolates and purifies (PE/EtOAc (v/v)=6/1), obtains faint yellow solid 312mg, yield：61.5%.
LC-MS:(pos.ion)m/z:186.1[M+1]+.
Step 5：((1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] are phonetic by compound (R) -3- Pyridine -3- bases) acetenyl)-N- cyclopropyl-phenyl formamides synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (0.16g, 0.40mmol) is dissolved in DMF (12mL), continuously add N- cyclopropyl -3- acetylenylbenzenes formamide (0.12g, 0.60mmol), cuprous iodide (0.016g, 0.08mmol), triethylamine (0.024g, 0.24mmol) and tetrakis triphenylphosphine palladium (0.024g,0.02mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room temperature, diatomite mistake Filter, concentrated solvent, saturated aqueous common salt (100mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, Concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=15/1), obtains faint yellow solid 60mg, yield：32.7%.
LC-MS:(pos.ion)m/z:456.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.57 (d, J=3.6Hz, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.89 (t, J=6.9Hz, 2H), 7.55 (t, J=7.7Hz, 1H), 6.89-6.70 (m, 1H), 6.21-6.05 (m, 1H), 5.75–5.57(m,1H),4.81–4.63(m,1H),4.62–4.52(m,0.5H),4.34–4.18(m,1H),4.17–4.04 (m,0.5H),3.71–3.60(m,0.5H),3.22–3.12(m,1H),3.00–2.91(m,0.5H),2.91–2.85(m,1H), 2.28–2.18(m,1H),2.17–2.08(m,1H),1.97–1.87(m,1H),1.66–1.52(m,1H),0.75–0.68(m, 2H),0.62–0.56(m,2H).
Embodiment 100
(R) -2- (3- ((1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] pyrimidin-3-yl) second Alkynyl) phenyl)-N- (4- (trifluoromethyl) phenyl) acetamide
Step 1：The synthesis of compound 2- (3- iodophenyls)-N- (4- (trifluoromethyl) phenyl) acetamide
3- iodobenzenes acetic acid (2.0g, 7.6mmol) is dissolved in DMF (40mL), HATU is then added into reaction solution (3.2g, 8.4mmol), DIPEA (DIPEA) (1.4mL, 8.4mmol, 0.78g/mL) and to trifluoromethylbenzene Amine (1.1mL, 8.4mmol, 1.28g/mL), reaction 3h is stirred at room temperature.After reaction completely, filter, concentration.Added into reaction solution Water (80mL), ethyl acetate extraction (60mL × 3), organic phase is with saturated common salt water washing (80mL × 3).Anhydrous sodium sulfate is done It is dry, filter, concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=12/1), obtain weak yellow liquid 2.8g, yield： 91%.
LC-MS:(pos.ion)m/z:406.01[M+1]+.
Step 2：Compound N-(4- (trifluoromethyl) phenyl) -2- (3- ((trimethyl silicon substrate) acetenyl) phenyl) acetamide Synthesis
2- (3- iodophenyls)-N- (4- (trifluoromethyl) phenyl) acetamide (1.5g, 3.7mmol) is dissolved in DMF (50mL), then add cuprous iodide (0.071g, 0.37mmol) and bi triphenyl phosphorus palladium chloride (0.26g, 0.37mmol). Replace nitrogen three times, under nitrogen protection, be slowly added to triethylamine (5.7mL, 41mmol, 0.728g/mL) and trimethylsilyl acetylene (0.85mL,5.9mmol,0.69g/mL).Nitrogen is protected, and is reacted at room temperature 24 hours.After reaction completely, filtering, filtrate is concentrated, is added Enter saturated aqueous common salt (60mL), ethyl acetate extraction (60mL × 3), merge organic phase, anhydrous sodium sulfate drying, filter, concentration. Silica gel column chromatography separating purification (PE/EtOAc (v/v)=20/1), obtains dark brown liquid 1.3g, yield：94%.
LC-MS(pos.ion)m/z:376.12[M+1]+.
Step 3：The synthesis of compound 2- (3- ethynyl phenyls)-N- (4- (trifluoromethyl) phenyl) acetamide
By N- (4- (trifluoromethyl) phenyl) -2- (3- ((trimethyl silicon substrate) acetenyl) phenyl) acetamide (1.3g, 3.5mmol) dissolving in methyl alcohol (30mL), then adds Anhydrous potassium carbonate (0.57g, 4.2mmol), and nitrogen is protected, and room temperature is anti- Answer 3h.After reaction completely, filtering, concentrated solvent.Into reaction solution plus water (100mL), ethyl acetate extract (60mL × 3).Close And organic phase, anhydrous sodium sulfate drying, concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=10/1), obtain yellowish Color solid 0.49g, yield：47.1%.
LC-MS:(pos.ion)m/z:304.09[M+1]+.
Step 4：Compound (R) -2- (3- ((1- (1- Antiepilepsirin -3- bases) -4- amino -1H- pyrazolos [3,4-d] Pyrimidin-3-yl) acetenyl) phenyl) and-N- (4- (trifluoromethyl) phenyl) acetamide synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (0.16g, 0.40mmol) is dissolved in DMF (12mL), continuously adds 2- (3- ethynyl phenyls)-N- (4- (trifluoromethyl) Phenyl) acetamide (0.185g, 0.60mmol), cuprous iodide (0.016mg, 0.08mmol), triethylamine (0.024g, 0.24mmol) and tetrakis triphenylphosphine palladium (0.024g, 0.02mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, are stopped Reaction, filtering, concentrated solvent, add saturated aqueous common salt (100mL), dichloromethane extraction (50mL × 3).Silica gel column chromatography separates Purify (DCM/MeOH (v/v)=35/1), obtain oily yellow solid 0.08g, yield：34.7%.
LC-MS:(pos.ion)m/z:574.21[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 10.63 (s, 1H), 8.27 (s, 1H), 7.84 (d, J=8.0Hz, 2H), 7.71 (s, 1H), 7.68 (d, J=8.1Hz, 2H), 7.64 (d, J=5.5Hz, 1H), 7.45 (s, 2H), 6.89-6.71 (m,1H),6.19–6.05(m,1H),5.74–5.58(m,1H),4.81–4.61(m,1H),4.62–4.50(m,0.5H), 4.41–4.20(m,1H),4.14–4.06(m,0.5H),3.77(s,2H),3.70–3.60(m,0.5H),3.23–3.11(m, 1H),2.96–2.86(m,0.5H),2.30–2.18(m,1H),2.14–2.06(m,1H),1.96–1.86(m,1H),1.67– 1.49(m,1H).
Embodiment 101
(R) ((4- amino -3- (imidazo [1,2-b] pyridazine -3- ethyl-acetylenes base) -1H- pyrazolos [3,4-d] are phonetic by 3- by -1- Pyridine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 3- ((trimethyl silicon substrate) acetenyl) imidazo [1,2-b] pyridazine
3- bromines imidazo [1,2-b] pyridazine (1g, 5.05mmol) is dissolved in THF (40mL), then into reaction solution Addition cuprous iodide (96mg, 0.505mmol), bi triphenyl phosphorus palladium chloride (292mg, 0.252mmol), triethylamine (7mL, 50.5mmol) and front three ethyl-acetylene silicon (1.4mL, 10.1mmol).Under nitrogen protection, 45 DEG C of stirring reaction 4h are heated to.Stop Reaction, filtering, concentration, water (100mL) is added into reaction solution, dichloromethane extracts (50mL × 3), anhydrous sodium sulfate drying, Filtering, concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=5/1), obtains faint yellow solid 409mg, yield： 37.6%.
LC-MS:(pos.ion)m/z:216.09[M+1]+.
Step 2：The synthesis of compound 3- acetenyls imidazo [1,2-b] pyridazine
3- ((trimethyl silicon substrate) acetenyl) imidazo [1,2-b] pyridazine (400mg, 1.857mmol) is dissolved in methanol (20mL), potassium hydroxide (310mg, 2.229mmol) is added in reaction solution.Replace nitrogen three times, under nitrogen protection, be stirred at room temperature React 5h.Stop reaction, filter, concentration.Add water (30mL), ethyl acetate extraction (20mL × 3), collect organic phase, anhydrous sulphur Sour sodium is dried, and is filtered, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=3/1), obtains faint yellow solid 110mg, yield：41.3%.
LC-MS(pos.ion)m/z:144.05[M+1]+.
Step 3：Compound (R) -1- (3- (4- amino -3- (imidazo [1,2-b] pyridazine -3- ethyl-acetylenes base) -1H- pyrazoles And [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (160mg, 0.4018mmol) is dissolved in DMF (15mL), continuously add 3- acetenyls imidazo [1,2-b] pyridazine (110mg, 0.602mmol), cuprous iodide (16mg, 0.0803mmol), triethylamine (24mg, 0.241mmol) and tetrakis triphenylphosphine palladium (24mg,0.020mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops reaction, filtering, concentrated solvent, adds saturation Saline solution (100mL), dichloromethane extraction (50mL × 3).Organic phase is collected, anhydrous sodium sulfate drying, is filtered, concentration.Thin layer Analysis isolates and purifies (DCM/MeOH (v/v)=16/1), obtains faint yellow solid 95mg, yield：57.1%.
LC-MS:(pos.ion)m/z:414.17[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.78–8.70(m,1H),8.36–8.31(m,2H),8.31–8.28 (m,1H),7.47(dd,J1=9.2Hz, J2=4.4Hz, 1H), 6.90-6.69 (m, 1H), 6.18-6.06 (m, 1H), 5.74- 5.60(m,1H),4.77–4.66(m,1H),4.63–4.53(m,0.5H),4.31–4.20(m,1H),4.15–4.05(m, 0.5H),3.74–3.62(m,0.5H),3.23–3.16(m,1H),3.04–2.92(m,0.5H),2.30–2.19(m,1H), 2.19–2.10(m,1H),1.97–1.89(m,1H),1.67–1.55(m,1H).
Embodiment 102
(R) -1- (3- (4- amino -3- (pyridine -2- ethyl-acetylenes base) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidines - 1- yls) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 2- ((trimethyl silicon substrate) acetenyl) pyridine
2- iodine pyridines (1.5g, 7.3mmol) are dissolved in THF (100mL), then add cuprous iodide (85mg, 0.44mmol) and bi triphenyl phosphorus palladium chloride (150mg, 0.22mmol).Replace nitrogen three times, under nitrogen protection, slowly add Enter diethylamine (8.3mL, 80mmol) and trimethylsilyl acetylene (1.7mL, 12mmol).Nitrogen is protected, and is reacted at room temperature 24 hours.Instead After answering completely, filtering, filtrate, saturated aqueous common salt-ethyl acetate extraction (60mL × 3), merging organic phase, anhydrous sodium sulfate are concentrated Dry, filter, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=60/1), obtains oily yellow liquid 1g, yield： 78%.
LC-MS:(pos.ion)m/z:176.08[M+1]+.
Step 2：The synthesis of compound 2- ethynyl pyridines
2- ((trimethyl silicon substrate) acetenyl) pyridine (1g, 5.70mmol) is dissolved in methanol (30mL), then added Anhydrous potassium carbonate (1g, 6.845mmol).Under nitrogen protection, reaction 4h is stirred at room temperature.After reaction completely, concentrated solvent, add full With saline solution (100mL), ethyl acetate extraction (50mL × 3), merge organic phase, anhydrous sodium sulfate drying, concentrated solvent.Silica gel Column chromatographic isolation and purification (PE/EtOAc (v/v)=8/1), obtains yellowish-brown liquid 220mg, yield：37.3%.
LC-MS:(pos.ion)m/z:104.04[M+1]+.
Step 3：((4- amino -3- (pyridine -2- ethyl-acetylenes base) -1H- pyrazolos [3,4-d] are phonetic by 3- by compound (R) -1- Pyridine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (140mg, 0.35mmol) is dissolved in DMF (15mL), continuously adds 2- ethynyl pyridines (60mg, 0.53mmol), and iodate is sub- Copper (14mg, 0.07mmol), triethylamine (21mg, 0.21mmol) and tetrakis triphenylphosphine palladium (21mg, 0.018mmol).Nitrogen Under protection, it is heated to 80 DEG C of reaction 15h and stops reaction, filtering, concentrated solvent, add saturated aqueous common salt (100mL), dichloromethane Extract (50mL × 3).Silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=18/1), obtains black solid 42mg, yield： 31.9%.
LC-MS:(pos.ion)m/z:374.17[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.67 (d, J=4.1Hz, 1H), 8.29 (s, 1H), 7.92 (t, J= 7.5Hz, 1H), 7.87 (d, J=7.6Hz, 1H), 7.52-7.45 (m, 1H), 6.88-6.72 (m, 1H), 6.19-6.04 (m, 1H),5.74–5.58(m,1H),4.78–4.64(m,1H),4.60–4.53(m,0.5H),4.32–4.20(m,1H),4.16– 4.05(m,0.5H),3.72–3.63(m,0.5H),3.23–3.14(m,1H),3.00–2.92(m,0.5H),2.28–2.19(m, 1H),2.18–2.08(m,1H),1.97–1.86(m,1H),1.65–1.53(m,1H).
Embodiment 103
(R) -1- (3- (4- amino -3- ((3- fluorophenyls) acetenyl) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidines - 1- yls) propyl- 2- alkene -1- ketone
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (140mg, 0.3516mmol) is dissolved in DMF (20mL), continuously adds the fluorobenzene of 1- acetenyls -3 (100mg, 0.7032mmol), Cuprous iodide (14mg, 0.0703mmol), triethylamine (23mg, 0.2109mmol) and tetrakis triphenylphosphine palladium (21mg, 0.01758mmol).Under nitrogen protection, it is heated to 80 DEG C of reaction 15h and stops reaction, filtering, concentrated solvent, add saturated common salt Water (100mL), dichloromethane extraction (50mL × 3).Silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=18/1), obtains Faint yellow solid 66mg, yield：48.0%.
LC-MS:(pos.ion)m/z:391.16[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.27 (s, 1H), 7.69 (d, J=9.4Hz, 1H), 7.58 (d, J= 7.6Hz,1H),7.51(dd,J1=14.1Hz, J2=7.8Hz, 1H), 7.35 (dd, J1=11.9Hz, J2=5.1Hz, 1H), 6.88–6.72(m,1H),6.18–6.06(m,1H),5.75–5.60(m,1H),4.75–4.63(m,1H),4.60–4.53(m, 0.5H),4.35–4.19(m,1H),4.13–4.05(m,0.5H),3.71–3.60(m,0.5H),3.22–3.12(m,1H), 2.99–2.86(m,0.5H),2.29–2.18(m,1H),2.17–2.07(m,1H),1.97–1.87(m,1H),1.65–1.52 (m,1H).
Embodiment 104
(R) ((4- amino -3- ((1- methyl isophthalic acid H- pyrazoles -4- bases) acetenyl) -1H- pyrazolos [3,4-d] are phonetic by 3- by -1- Pyridine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of the iodo- 1- methyl isophthalic acids H- pyrazoles of compound 4-
4- iodine pyrazoles (2g, 10.311mmol) is dissolved in DMF (50mL), at 0 DEG C add sodium hydride (1.25g, 30.933mmol), stirring reaction 30min.Iodomethane (1.3mL, 20.622mmol) is slowly dropped in above-mentioned solution, risen to Room temperature, stirring reaction 22 hours.After reaction completely, filtering, filtrate is concentrated, is diluted with water, ethyl acetate extraction (80mL × 3), Organic phase is collected, anhydrous sodium sulfate drying, filtering, concentrates filtrate.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=18/ 1) weak yellow liquid 1.37g, yield, are obtained：63.9%.
LC-MS:(pos.ion)m/z:208.95[M+1]+.
Step 2：The synthesis of compound 1- methyl -4- ((trimethyl silicon substrate) acetenyl) -1H- pyrazoles
The iodo- 1- methyl isophthalic acids H- pyrazoles (1.37g, 6.59mmol) of 4- are dissolved in THF (40mL), then sequentially add iodine Change cuprous (75mg, 0.198mmol) and bi triphenyl phosphorus palladium chloride (140mg, 0.198mmol), replace nitrogen three times, nitrogen Under protection, diethylamine (7.5mL, 72.5mmol) and trimethylsilyl acetylene (1.9mL, 13.2mmol, 0.69g/mL) are slowly added to. Reaction 20h is stirred at room temperature.After reaction completely, saturated aqueous common salt (100mL) is added, ethyl acetate extraction (50mL × 3), is associated with Machine phase, anhydrous sodium sulfate drying, concentrated solvent.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=20/1), is obtained yellowish Color liquid 684mg, yield：58.2%.
LC-MS:(pos.ion)m/z:179.09[M+1]+.
Step 3：The synthesis of compound 4- acetenyl -1- methyl isophthalic acid H- pyrazoles
1- methyl -4- ((trimethyl silicon substrate) acetenyl) -1H- pyrazoles (685mg, 3.84mmol) is dissolved in methanol In (30mL), Anhydrous potassium carbonate (640mg, 4.61mmol) is then added, under nitrogen protection, reaction 3.5h is stirred at room temperature.Stop Reaction, concentration, saturated aqueous common salt (100mL) is added, ethyl acetate extraction (50mL × 3) merges organic phase, and anhydrous sodium sulfate is done It is dry, concentrated solvent.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=15/1), obtains weak yellow liquid 196mg, yield： 48%.
LC-MS:(pos.ion)m/z:107.05[M+1]+.
Step 4：Compound (R) -1- (3- (4- amino -3- ((1- methyl isophthalic acid H- pyrazoles -4- bases) acetenyl) -1H- pyrazoles And [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (170mg, 0.4269mmol) is dissolved in DMF (20mL), continuously add 4- acetenyl -1- methyl isophthalic acid H- pyrazoles (80mg, 0.64mmol), cuprous iodide (17mg, 0.08mmol), triethylamine (26mg, 0.26mmol) and tetrakis triphenylphosphine palladium (25mg, 0.02mmol).Under nitrogen protection, it is heated to 80 DEG C of reaction 15h and stops reaction, filtering, concentrated solvent, add saturated aqueous common salt (100mL), dichloromethane extraction (50mL × 3).Silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=18/1), obtains light Yellow solid 77mg, yield：47.9%.
LC-MS:(pos.ion)m/z:377.18[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.25(s,1H),8.21(s,1H),7.84(s,1H),6.87– 6.71(m,1H),6.17–6.05(m,1H),5.74–5.59(m,1H),4.71–4.61(m,1H),4.58–4.50(m,0.5H), 4.34–4.17(m,1H),4.12–4.05(m,0.5H),3.89(s,3H),3.67–3.58(m,0.5H),3.21–3.10(m, 1H),2.96–2.88(m,0.5H),2.26–2.16(m,1H),2.14–2.05(m,1H),1.95–1.86(m,1H),1.63– 1.51(m,1H).
Embodiment 105
(R) ((4- amino -3- ((1- benzyl -1H- pyrazoles -4- bases) acetenyl) -1H- pyrazolos [3,4-d] are phonetic by 3- by -1- Pyridine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of the iodo- 1H- pyrazoles of compound 1- benzyls -4-
4- iodine pyrazoles (2g, 10.311mmol) is dissolved in acetone (40mL), then add Anhydrous potassium carbonate (4.3g, 30.93mmol) and bromobenzyl (1.9mL, 15.47mmol, 1.44g/mL).Replace nitrogen three times, under nitrogen protection, be heated to reflux anti- Answer 24 hours.After reaction completely, filtering, filtrate is concentrated, silica gel column chromatography separating purification (PE/EtOAc (v/v)=50/1), is obtained To weak yellow liquid 2.8g, yield：96%.
LC-MS:(pos.ion)m/z:284.98[M+1]+.
Step 2：The synthesis of compound 1- benzyls -4- ((trimethyl silicon substrate) acetenyl) -1H- pyrazoles
The iodo- 1H- pyrazoles (1.3g, 4.6mmol) of 1- benzyls -4- are dissolved in THF (40mL), then sequentially add iodate Cuprous (52mg, 0.27mmol) and bi triphenyl phosphorus palladium chloride (96mg, 0.14mmol), displacement nitrogen three times, protect by nitrogen Under, it is slowly added to diethylamine (5.2mL, 50mmol) and trimethylsilyl acetylene (1.3mL, 9.2mmol, 0.69g/mL).Room temperature is stirred Mix reaction 24h.After reaction completely, saturated aqueous common salt (100mL) is added, ethyl acetate extraction (60mL × 3), merges organic phase, Anhydrous sodium sulfate drying, concentrated solvent.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=50/1), obtains light yellow liquid Body 1.1g, yield：94%.
LC-MS:(pos.ion)m/z:255.12[M+1]+.
Step 3：The synthesis of compound 1- benzyl -4- acetenyl -1H- pyrazoles
1- benzyls -4- ((trimethyl silicon substrate) acetenyl) -1H- pyrazoles (1.2g, 4.7mmol) is dissolved in methanol (35mL) In, Anhydrous potassium carbonate (780mg, 5.7mmol) is then added, under nitrogen protection, reaction 3.5h is stirred at room temperature.Stop reaction, it is dense Contracting, saturated aqueous common salt (100mL) is added, ethyl acetate extraction (50mL × 3), merges organic phase, anhydrous sodium sulfate drying, concentration Solvent.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=40/1), obtains weak yellow liquid 410mg, yield：48%.
LC-MS:(pos.ion)m/z:183.08[M+1]+.
Step 4：Compound (R) -1- (3- (4- amino -3- ((1- benzyl -1H- pyrazoles -4- bases) acetenyl) -1H- pyrazoles And [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (140mg, 0.3516mmol) is dissolved in DMF (15mL), continuously add 1- benzyl -4- acetenyl -1H- pyrazoles (130mg, 0.7032mmol), cuprous iodide (14mg, 0.0703mmol), triethylamine (21mg, 0.210mmol) and tetrakis triphenylphosphine palladium (21mg,0.0175mmol).Under nitrogen protection, it is heated to 80 DEG C of reaction 15h and stops reaction, filtering, concentrated solvent, add saturation Saline solution (100mL), dichloromethane extraction (50mL × 3).Silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=15/1), Obtain faint yellow solid 49mg, yield：30.8%.
LC-MS:(pos.ion)m/z:453.21[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.37(s,1H),8.25(s,1H),7.89(s,1H),7.38(t,J =7.2Hz, 2H), 7.33 (d, J=7.0Hz, 1H), 7.30 (t, J=7.8Hz, 2H), 6.87-6.71 (m, 1H), 6.17-6.05 (m,1H),5.74–5.59(m,1H),5.39(s,2H),4.71–4.61(m,1H),4.58–4.51(m,0.5H),4.35–4.17 (m,1H),4.12–4.04(m,0.5H),3.67–3.60(m,0.5H),3.19–3.10(m,1H),2.96–2.87(m,0.5H), 2.27–2.16(m,1H),2.14–2.05(m,1H),1.96–1.86(m,1H),1.62–1.51(m,1H).
Embodiment 106
(R) -1- (3- (4- amino -3- ((1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) acetenyl) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 2- ((the iodo- 1H- pyrazol-1-yls of 4-) methyl) pyridine
4- iodine pyrazoles (2g, 10.33mmol) is dissolved in acetone (40mL), then add potassium carbonate (4.3g, 30.93mmol) and 2- (bromomethyl) pyridine hydrobromide salt (3.4g, 13.40mmol).Nitrogen is protected, and heating reflux reaction 24 is small When.Stop heating, be cooled to room temperature, filter, concentrated solvent.Add water (180mL), ethyl acetate extraction (80mL × 3).Collect Organic phase, anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=12/1), is obtained White solid 2.2g, yield：75%.
LC-MS:(pos.ion)m/z:285.98[M+1]+.
Step 2：The synthesis of compound 2- ((4- ((trimethyl silicon substrate) acetenyl) -1H- pyrazol-1-yls) methyl) pyridine
2- ((the iodo- 1H- pyrazol-1-yls of 4-) methyl) pyridine (1.2g, 4.2mmol) is dissolved in dry THF (50mL), then add cuprous iodide (48mg, 0.25mmol) and bi triphenyl phosphorus palladium chloride (90mg, 0.13mmol).Put Change nitrogen three times, under nitrogen protection, be slowly added to diethylamine (4.8mL, 46mmol, 0.71g/mL) and trimethylsilyl acetylene (1.2mL,8.4mmol,0.69g/mL).Nitrogen is protected, and is reacted at room temperature 24 hours.After reaction completely, filtering, filtrate is concentrated, is added Enter saturated aqueous common salt (60mL), ethyl acetate extraction (60mL × 3), merge organic phase, anhydrous sodium sulfate drying, filter, concentration. Silica gel column chromatography separating purification (PE/EtOAc (v/v)=6/1), obtains brown liquid 0.95g, yield：86.3%.
LC-MS:(pos.ion)m/z:256.12[M+1]+.
Step 3：The synthesis of compound 2- ((4- acetenyl -1H- pyrazol-1-yls) methyl) pyridine
2- ((4- ((trimethyl silicon substrate) acetenyl) -1H- pyrazol-1-yls) methyl) pyridine (1.15g, 4.5mmol) is molten Solution then adds Anhydrous potassium carbonate (0.75g, 5.4mmol) in methanol (40mL).Under nitrogen protection, reaction 4h is stirred at room temperature. After reaction completely, filtering, concentrated solvent.It is diluted with water (60mL), ethyl acetate extraction (50mL × 3), merges organic phase, it is anhydrous Sodium sulphate is dried, concentrated solvent.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=6/1), obtains weak yellow liquid 0.75g, yield：90.9%.
LC-MS:(pos.ion)m/z:184.08[M+1]+.
Step 4：Compound (R) -1- (3- (4- amino -3- ((1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) acetylene Base) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (0.15g, 0.37mmol) is dissolved in DMF (12mL), continuously adds 2- ((4- acetenyl -1H- pyrazol-1-yls) methyl) pyridine (0.14g, 0.75mmol), cuprous iodide (0.015g, 0.075mmol), triethylamine (0.022g, 0.22mmol) and four (triphens Base phosphine) palladium (0.022g, 0.019mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room temperature, silicon Diatomaceous earth filters, concentrated solvent, adds saturated aqueous common salt (100mL), and dichloromethane extracts (50mL × 3), anhydrous sodium sulfate drying, Filtering, concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=35/1), obtains faint yellow solid 73mg, yield： 42.7%.
LC-MS:(pos.ion)m/z:454.21[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.55 (d, J=4.4Hz, 1H), 8.40 (s, 1H), 8.25 (s, 1H), 7.90 (s, 1H), 7.81 (td, J=7.7,1.6Hz, 1H), 7.34 (dd, J1=7.0Hz, J2=5.1Hz, 1H), 7.18 (d, J=7.8Hz, 1H), 6.87-6.68 (m, 1H), 6.18-6.02 (m, 1H), 5.74-5.58 (m, 1H), 5.49 (s, 2H), 4.76–4.61(m,1H),4.58–4.50(m,0.5H),4.33–4.16(m,1H),4.16–3.99(m,0.5H),3.70–3.59 (m,0.5H),3.22–3.08(m,1H),2.98–2.87(m,0.5H),2.28–2.15(m,1H),2.15–2.05(m,1H), 1.96–1.86(m,1H),1.65–1.50(m,1H).
Embodiment 107
(R) -1- (3- (4- amino -3- ((3- Phenoxyphenyls) acetenyl) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of the bromo- 3- phenoxy groups benzene of compound 1-
M-dibromobenzene (3.9g, 17mmol) and phenol (1.3g, 14mmol) are dissolved in 1-METHYLPYRROLIDONE (45mL) In, cupric oxide (0.11g, 1.4mmol) and cesium carbonate (5g, 15mmol) are then added, nitrogen protection, is heated to 195 DEG C of reactions 50min.Stop heating, be cooled to room temperature, diatomite filtering, be diluted with water (100mL).Ethyl acetate extracts (80mL × 3), receives Collect organic phase, anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (PE), obtains weak yellow liquid 3.4g, Yield：96%.
LC-MS:(pos.ion)m/z:249.98[M+1]+.
Step 2：The synthesis of compound trimethyl ((3- Phenoxyphenyls) acetenyl) silane
The bromo- 3- phenoxy groups benzene (1.5g, 6.0mmol) of 1- are dissolved in THF (50mL), then add cuprous iodide (70mg, 0.36mmol) and bi triphenyl phosphorus palladium chloride (130mg, 0.18mmol).Replace nitrogen three times, under nitrogen protection, It is slowly added to diethylamine (7mL, 60mmol) and trimethylsilyl acetylene (1.5mL, 9mmol).Nitrogen is protected, and room temperature reaction 24 is small When.After reaction completely, diatomite filtering, concentration filtrate, addition saturated aqueous common salt (60mL), ethyl acetate extraction (60mL × 3), Merge organic phase, anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (PE), obtains weak yellow liquid 150mg, yield：9.4%.
LC-MS:(pos.ion)m/z:267.12[M+1]+.
Step 3：The synthesis of compound 1- acetenyl -3- phenoxy group benzene
Trimethyl ((3- Phenoxyphenyls) acetenyl) silane (250mg, 0.93mmol) is dissolved in methanol (20mL), Then Anhydrous potassium carbonate (156mg, 1.12mmol) is added.Under nitrogen protection, reaction 5.5h is stirred at room temperature.After reaction completely, mistake Filter, concentrated solvent, is diluted with water (50mL), ethyl acetate extraction (50mL × 3), merges organic phase, and anhydrous sodium sulfate drying is dense Contracting solvent.Silica gel column chromatography separating purification (PE), obtains weak yellow liquid 119mg, yield：65.3%.
LC-MS:(pos.ion)m/z:195.08[M+1]+.
Step 4：Compound (R) -1- (3- (4- amino -3- ((3- Phenoxyphenyls) acetenyl) -1H- pyrazolos [3,4- D] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (150mg, 0.37mmol) is dissolved in DMF (12mL), continuously add 1- acetenyl -3- phenoxy groups benzene (109mg, 0.56mmol), cuprous iodide (15mg, 0.07mmol), triethylamine (20mg, 0.22mmol) and tetrakis triphenylphosphine palladium (22mg, 0.018mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stop heating, are cooled to room temperature, diatomite filters, and concentration is molten Agent, saturated aqueous common salt (50mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration.Silicagel column Chromatography purifies (DCM/MeOH (v/v)=40/1), obtains faint yellow solid 48mg, yield：27.4%.
LC-MS:(pos.ion)m/z:465.20[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.26 (s, 1H), 7.49 (d, J=1.6Hz, 1H), 7.48-7.45 (m, 1H), 7.44-7.43 (m, 1H), 7.43-7.36 (m, 2H), 7.19 (t, J=7.4Hz, 1H), 7.14-7.10 (m, 1H), 7.09(s,1H),7.07(s,1H),6.90–6.68(m,1H),6.20–6.02(m,1H),5.76–5.56(m,1H),4.79– 4.63(m,1H),4.59–4.49(m,0.5H),4.37–4.18(m,1H),4.13–4.04(m,0.5H),3.70–3.59(m, 0.5H),3.22–3.10(m,1H),2.97–2.89(m,0.5H),2.28–2.16(m,1H),2.16–2.05(m,1H),1.96– 1.84(m,1H),1.66–1.52(m,1H).
Embodiment 108
(R) -1- (3- (4- amino -3- ((1- (pyridin-3-yl methyl) -1H- pyrazoles -4- bases) acetenyl) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 3- ((the iodo- 1H- pyrazol-1-yls of 4-) methyl) pyridine
4- iodine pyrazoles (1.7g, 8.8mmol) is dissolved in acetone (40mL), then add potassium carbonate (3.7g, 36mmol) and 3- (bromomethyl) pyridine hydrobromide salt (2.9g, 11mmol).Nitrogen is protected, heating reflux reaction 24 hours.Stop Heating, is cooled to room temperature, filters, concentrated solvent.Add water (180mL), ethyl acetate extraction (80mL × 3).Collect organic phase, Anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=3/1), obtains pale yellow colored solid Body 1.1g, yield：44%.
LC-MS:(pos.ion)m/z:285.98[M+1]+.
Step 2：The synthesis of compound 3- ((4- ((trimethyl silicon substrate) acetenyl) -1H- pyrazol-1-yls) methyl) pyridine
3- ((the iodo- 1H- pyrazol-1-yls of 4-) methyl) pyridine (0.7g, 2.4mmol) is dissolved in dry THF (25mL), then add cuprous iodide (28mg, 0.15mmol) and bi triphenyl phosphorus palladium chloride (51mg, 0.07mmol).Put Change nitrogen three times, under nitrogen protection, be slowly added to diethylamine (2.8mL, 27mmol, 0.71g/mL) and trimethylsilyl acetylene (0.7mL,4.9mmol,0.69g/mL).Nitrogen is protected, and is reacted at room temperature 24 hours.After reaction completely, filtering, filtrate is concentrated, is added Enter saturated aqueous common salt (60mL), ethyl acetate extraction (60mL × 3), merge organic phase, anhydrous sodium sulfate drying, filter, concentration. Silica gel column chromatography separating purification (PE/EtOAc (v/v)=3/1), obtains brown liquid 0.56g, yield：89.3%.
LC-MS:(pos.ion)m/z:256.12[M+1]+.
Step 3：The synthesis of compound 3- ((4- acetenyl -1H- pyrazol-1-yls) methyl) pyridine
3- ((4- ((trimethyl silicon substrate) acetenyl) -1H- pyrazol-1-yls) methyl) pyridine (0.54g, 2.14mmol) is molten Solution then adds Anhydrous potassium carbonate (0.36g, 2.57mmol) in methanol (40mL).Under nitrogen protection, reaction is stirred at room temperature 3h.After reaction completely, filtering, concentrated solvent.It is diluted with water (60mL), ethyl acetate extraction (50mL × 3), merges organic phase, Anhydrous sodium sulfate drying, concentrated solvent.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=3/1), obtains weak yellow liquid 253mg, yield：64.4%.
LC-MS:(pos.ion)m/z:184.08[M+1]+.
Step 4：Compound (R) -1- (3- (4- amino -3- ((1- (pyridin-3-yl methyl) -1H- pyrazoles -4- bases) acetylene Base) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (0.16g, 0.40mmol) is dissolved in DMF (12mL), continuously adds 3- ((4- acetenyl -1H- pyrazol-1-yls) methyl) pyridine (0.11g, 0.60mmol), cuprous iodide (15mg, 0.08mmol), triethylamine (25mg, 0.24mmol) and four (triphenylphosphines) Palladium (23mg, 0.02mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room temperature, diatomite mistake Filter, concentrated solvent, saturated aqueous common salt (100mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, Concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=35/1), obtains faint yellow solid 58mg, yield：31.8%.
LC-MS:(pos.ion)m/z:454.21[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.57 (d, J=1.7Hz, 1H), 8.54 (dd, J1=4.7Hz, J2 =1.3Hz, 1H), 8.41 (s, 1H), 8.24 (s, 1H), 7.91 (s, 1H), 7.71 (d, J=7.9Hz, 1H), 7.41 (dd, J= 7.8,4.8Hz,1H),6.87–6.69(m,1H),6.19–6.03(m,1H),5.75–5.58(m,1H),5.45(s,2H), 4.71–4.61(m,1H),4.56–4.48(m,0.5H),4.34–4.16(m,1H),4.11–4.03(m,0.5H),3.67–3.58 (m,0.5H),3.20–3.11(m,1H),2.97–2.87(m,0.5H),2.25–2.16(m,1H),2.13–2.05(m,1H), 1.95–1.86(m,1H),1.63–1.52(m,1H).
Embodiment 109
(R) -1- (3- (4- amino -3- ((1- (pyridin-4-yl methyl) -1H- pyrazoles -4- bases) acetenyl) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 4- ((the iodo- 1H- pyrazol-1-yls of 4-) methyl) pyridine
4- iodine pyrazoles (1.3g, 6.7mmol) is dissolved in acetone (40mL), then add potassium carbonate (2.8g, 20.0mmol) and 4- (bromomethyl) pyridine hydrobromide salt (2.2g, 8.7mmol).Nitrogen is protected, heating reflux reaction 24 hours. Stop heating, be cooled to room temperature, filter, concentrated solvent.Add water (150mL), ethyl acetate extraction (60mL × 3).Collection has Machine phase, anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=4/1), is obtained yellowish Color solid 412mg, yield：22%.
LC-MS:(pos.ion)m/z:285.98[M+1]+.
Step 2：The synthesis of compound 4- ((4- ((trimethyl silicon substrate) acetenyl) -1H- pyrazol-1-yls) methyl) pyridine
4- ((the iodo- 1H- pyrazol-1-yls of 4-) methyl) pyridine (412mg, 1.44mmol) is dissolved in dry THF (20mL), then add cuprous iodide (17mg, 0.08mmol) and bi triphenyl phosphorus palladium chloride (31mg, 0.04mmol).Put Change nitrogen three times, under nitrogen protection, be slowly added to diethylamine (1.6mL, 15.8mmol, 0.71g/mL) and trimethylsilyl acetylene (0.4mL,2.9mmol,0.69g/mL).Nitrogen is protected, and is reacted at room temperature 24 hours.After reaction completely, filtering, filtrate is concentrated, is added Enter saturated aqueous common salt (50mL), ethyl acetate extraction (50mL × 3), merge organic phase, anhydrous sodium sulfate drying, filter, concentration. Silica gel column chromatography separating purification (PE/EtOAc (v/v)=3/1), obtains brown liquid 360mg, yield：97.5%.
LC-MS:(pos.ion)m/z:256.12[M+1]+.
Step 3：The synthesis of compound 4- ((4- acetenyl -1H- pyrazol-1-yls) methyl) pyridine
4- ((4- ((trimethyl silicon substrate) acetenyl) -1H- pyrazol-1-yls) methyl) pyridine (360mg, 1.4mmol) is molten Solution then adds Anhydrous potassium carbonate (235mg, 1.7mmol) in methanol (20mL).Under nitrogen protection, reaction 4h is stirred at room temperature. After reaction completely, filtering, concentrated solvent.It is diluted with water (50mL), ethyl acetate extraction (50mL × 3), merges organic phase, it is anhydrous Sodium sulphate is dried, concentrated solvent.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=4/1), obtains weak yellow liquid 192mg, yield：74.3%.
LC-MS:(pos.ion)m/z:184.08[M+1]+.
Step 4：Compound (R) -1- (3- (4- amino -3- ((1- (pyridin-4-yl methyl) -1H- pyrazoles -4- bases) acetylene Base) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) and propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (160mg, 0.40mmol) is dissolved in DMF (12mL), continuously adds 4- ((4- acetenyl -1H- pyrazol-1-yls) methyl) pyridine (110mg, 0.60mmol), cuprous iodide (15mg, 0.07mmol), triethylamine (25mg, 0.24mmol) and four (triphenylphosphines) Palladium (23mg, 0.02mmol).Under nitrogen protection, 80 DEG C of reaction 15h are heated to, stops heating, is cooled to room temperature, diatomite mistake Filter, concentrated solvent, saturated aqueous common salt (100mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, Concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=35/1), obtains faint yellow solid 74mg, yield：40.6%.
LC-MS:(pos.ion)m/z:454.21[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)8.56(dd,J1=4.6Hz, J2=1.3Hz, 2H), 8.42 (s, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.19 (d, J=5.8Hz, 2H), 6.86-6.69 (m, 1H), 6.17-6.05 (m, 1H),5.73–5.59(m,1H),5.48(s,2H),4.74–4.61(m,1H),4.59–4.51(m,0.5H),4.33–4.17(m, 1H),4.14–4.01(m,0.5H),3.69–3.59(m,0.5H),3.21–3.11(m,1H),2.99–2.87(m,0.5H), 2.25–2.16(m,1H),2.15–2.04(m,1H),1.95–1.85(m,1H),1.64–1.51(m,1H).
Embodiment 110
(R) -1- (3- (4- amino -3- ((1- hydroxy-cyclohexyls) acetenyl) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Piperidin-1-yl) propyl- 2- alkene -1- ketone
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (100mg, 0.25mmol) is dissolved in DMF (15mL), continuously adds 1- ethynylcyclohexanols (50mg, 0.38mmol), iodate Cuprous (10mg, 0.050mmol), triethylamine (15mg, 0.15mmol) and tetrakis triphenylphosphine palladium (15mg, 0.013mmol).Nitrogen Under gas shielded, 80 DEG C of reaction 15h are heated to, stop heating, be cooled to room temperature, diatomite filtering, concentrated solvent, add saturation food Salt solution (80mL), dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains oily yellow solid 72mg, yield：72.6%.LC-MS:(pos.ion)m/z:395.2 [M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)8.25(s,1H),6.91–6.64(m,1H),6.20–6.02(m, 1H),5.82(s,1H),5.75–5.58(m,1H),4.71–4.57(m,1H),4.57–4.45(m,0.5H),4.39–4.13(m, 1H),4.10–3.97(m,0.5H),3.75–3.50(m,0.5H),3.20–3.07(m,1H),2.96–2.82(m,0.5H), 2.29–2.15(m,1H),2.13–2.03(m,1H),1.96–1.90(m,1H),1.90–1.81(m,2H),1.75–1.60(m, 4H),1.60–1.56(m,1H),1.55–1.38(m,4H).
Embodiment 111
3- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) benzonitrile
3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -4- amine (250mg, 0.824mmol) is dissolved in In DMF (15mL), ioxynil (207mg, 0.906mmol) between then being added into reaction solution, cuprous iodide (32mg, 0.165mmol) and cesium carbonate (540mg, 1.64mmol).Under nitrogen protection, heating reflux reaction 24h.Stop heating, cool down, Concentrated solvent, water (100mL) is added into reaction solution, dichloromethane (50mL × 3) extraction, merges organic phase, anhydrous sodium sulfate Dry, filter, concentration, silica gel column chromatography separating purification (DCM/MeOH (v/v)=30/1), analysed containing a small amount of impurity, then through thin layer (DCM/MeOH (v/v)=40/1) is isolated and purified, obtains white solid 8mg, yield：4.5%.
LC-MS:(pos.ion)m/z:405.14[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.75 (s, 1H), 8.63 (d, J=7.8Hz, 1H), 8.44 (s, 1H), 7.83 (d, J=7.2Hz, 2H), 7.79 (d, J=7.9Hz, 2H), 7.46 (t, J=7.5Hz, 2H), 7.23 (s, 1H), 7.21 (d, J=8.3Hz, 2H), 7.16 (d, J=7.8Hz, 2H)
Embodiment 112
(R)-N- (4- (4- amino -1- (1- cyano piperidine -3- bases) -1H- pyrazolos [3,4-d] pyrimidin-3-yl) phenyl) Methanesulfomide
Step 1：The synthesis of iodo- 1H- pyrazolos [3,4-d] pyrimidine -4- amine of compound 3-
1H- pyrazolos [3,4-d] pyrimidine -4- amine (18.0g, 130.54mmol) is dissolved in DMF (150mL), then It is slowly added into N- N-iodosuccinimides (45g, 195.81mmol, Aldrich) into above-mentioned solution, stirring reaction 12 at 80 DEG C Hour.Stopping heating, cooling, water (200mL) is added into reaction solution, filter, wash (80mL), ethanol (60mL) is washed, and is dried, Obtain gray solid 25.8g, yield：75.7%.LC-MS:(pos.ion)m/z:261.9[M+1]+.
Step 2：The synthesis of compound (S)-tert-butyl group 3- ((mesyl) epoxide) piperidines -1- carboxylates
(S)-tert-butyl group 3- hydroxy piperidine -1- carboxylates (20.0g, 97.1mmol) are dissolved in dichloromethane (200mL) In, triethylamine (18mL, 126mmol) is then added into the solution, mesyl chloride (8.3mL, 107mmol) is added under ice-water bath With DMAP (1.21g, 9.71mmol).It is stirred at room temperature 12 hours, dichloromethane (150mL) extraction, saturated common salt Wash (60mL), anhydrous sodium sulfate drying, remove solvent, silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/ under reduced pressure V)=6/1), white solid 21g, yield are obtained：77.4%.
LC-MS(pos.ion)m/z:224.1(M-55).
Step 3：Compound (R)-tert-butyl group 3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidines - The synthesis of 1- carboxylates
Iodo- 1H- pyrazolos [3, the 4-d] pyrimidine -4- amine (1.14g, 4.37mmol) of 3- are dissolved in DMF (100mL), so (S)-tert-butyl group 3- ((mesyl) epoxide) piperidines -1- carboxylates (3.66g, 13.10mmol), carbon are added in backward reaction solution Sour caesium (4.27g, 13.10mmol) and DMAP (0.53g, 4.37mmol).Stir 8 hours, reacted at 90 DEG C Afterwards, remove DMF under reduced pressure, dichloromethane (150mL) extraction, saturated common salt washing (60mL), anhydrous sodium sulfate drying, remove under reduced pressure Solvent, silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains product 1.28g, yield：66%.
LC-MS(pos.ion)m/z:445.27[M+1]+.
Step 4：The synthesis of the iodo- 1- of compound (R) -3- (piperidines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -4- amine
By (R)-tert-butyl group 3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidines -1- carboxylates (1.28g, 2.88mmol) is dissolved in dioxane (6mL), and hydrochloric acid (4N, 6mL) is then added into reaction solution, is stirred at room temperature 16 hours, after having reacted, dilute sodium hydrate aqueous solution is added, is adjusted to pH=9, dichloromethane (150mL) extraction, saturated common salt Wash (60mL), anhydrous sodium sulfate drying, remove solvent, silica gel column chromatography separating purification (DCM/MeOH (v/v)=12/ under reduced pressure 1-6/1), product 840mg, yield are obtained：84.7%.
LC-MS(pos.ion)m/z:345.02[M+1]+.
Step 5：Compound (R) -3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidines -1- formonitrile HCNs Synthesis
The iodo- 1- of (R) -3- (piperidines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -4- amine (3g, 8.716mmol) is dissolved in In DMF (80mL), cesium carbonate (11.6g, 34.868mmol) is added.Be slowly added at 0 DEG C cyanogen bromide (1.9g, 17.434mmol), continue stirring reaction 30min, reaction 3 hours is stirred at room temperature.Stop reaction, filtering, concentrate filtrate, add full With saline solution (150mL), ethyl acetate extraction (100mL × 3), anhydrous sodium sulfate drying, concentration, silica gel column chromatography separating purification (DCM/MeOH (v/v)=60/1), obtains faint yellow solid 770mg, yield：24%.
LC-MS:(pos.ion)m/z:370.02[M+1]+.
Step 6：The synthesis of compound N-(3- bromophenyls) Methanesulfomide
M-bromoaniline (3.5g, 20mmol) is dissolved in dichloromethane (80mL), then add pyridine (8.3mL, 100mmol, 0.981g/mL), react at room temperature 20h.Stop reaction, saturated common salt washing (50mL × 3), anhydrous sodium sulfate drying. Filtering, concentration, silica gel column chromatography separating purification (PE/EtOAc (v/v)=4/1), obtains white solid 2.04g, yield：40%.
LC-MS:(pos.ion)m/z:249.95[M+1]+.
Step 7：Compound N-(3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- bases) phenyl) methylsulfonyl The synthesis of amine
N- (3- bromophenyls) Methanesulfomides (900mg, 3.59mmol) are dissolved in Isosorbide-5-Nitrae-dioxane (25mL), add connection Boric acid pinacol ester (1.65g, 6.477mmol), 1,1'- double Diphenyl phosphino ferrocene palladium chlorides (265mg, 0.359mmol) With potassium acetate (1.1g, 10.79mmol).Replace nitrogen three times, under nitrogen protection, be heated to 90 DEG C and react 24 hours.Stop anti- Should, water (50mL) is added, dichloromethane (50mL × 3) extraction, merges organic phase, anhydrous sodium sulfate drying, filters, concentration.Silicon Plastic column chromatography isolates and purifies (PE/EtOAc (v/v)=3/1), obtains faint yellow solid 720mg, yield：67.32%.
LC-MS:(pos.ion)m/z:298.12[M+1]+.
Step 8：((4- amino -1- (1- cyano piperidine -3- bases) -1H- pyrazolos [3,4-d] are phonetic by 4- by compound (R)-N- Pyridine -3- bases) phenyl) Methanesulfomide synthesis
By (R) -3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidines -1- formonitrile HCNs (135mg, The in the mixed solvent of Isosorbide-5-Nitrae-dioxane (15mL) and water (5mL) 0.365mmol) is dissolved in, continuously adds N- (3- (4,4,5,5- Tetramethyl -1,3,2- dioxaborolan -2- bases) phenyl) Methanesulfomide (165mg, 0.548mmol), Anhydrous potassium carbonate The double Diphenyl phosphino ferrocene palladium chlorides (27mg, 0.036mmol) of (150mg, 1.09mmol) and 1,1'-.Under nitrogen protection, add Heat reacts 13h to 120 DEG C.Stop reaction, filtering, concentrated solvent, add saturated aqueous common salt (100mL), dichloromethane (60mL × 3) extract.Silica gel thin-layer analysis isolates and purifies (DCM/MeOH (v/v)=12/1), obtains oily yellow solid 38mg, yield： 25.3%.
LC-MS:(pos.ion)m/z:413.14[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 9.94 (s, 2H), 8.28 (s, 1H), 7.52 (d, J=7.9Hz, 1H), 7.50 (s, 1H), 7.42 (d, J=7.3Hz, 1H), 7.33 (d, J=7.7Hz, 1H), 4.92-4.83 (m, 1H), 3.65 (d, J=9.5Hz, 1H), 3.56-3.48 (m, 1H), 3.44-3.39 (m, 1H), 3.21-3.13 (m, 1H), 3.06 (s, 3H), 2.22–2.13(m,1H),2.13–2.06(m,1H),1.95–1.87(m,1H),1.86–1.76(m,1H).
Embodiment 113
3- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexanecarbonitrile
Step 1：The synthesis of compound 3- hydroxy cyclohexylphenyl formonitrile HCNs
3- oxocyclohex formonitrile HCN (1.5g, 12mmol) is dissolved in absolute methanol (45mL), sodium borohydride is added at 0 DEG C (0.8g,21mmol,Aldrich).Stirring reaction 4 hours at room temperature, stop reaction, it is molten that saturated ammonium chloride is added into reaction solution Liquid (200mL).Ethyl acetate extracts three times, merges organic phase, anhydrous sodium sulfate drying, filters, concentration, obtains faint yellow oily Liquid 1.45g, yield：95%.
LC-MS:(pos.ion)m/z:126.08[M+1]+.
Step 2：The synthesis of chemical compound 3-cyano cyclohexyl methanesulfonates
3- hydroxy cyclohexylphenyls formonitrile HCN (1.45g, 11.6mmol) is dissolved in dichloromethane (50mL), then into reaction solution Triethylamine (2.11mL, 15.0mmol) is added, mesyl chloride (1.2mL, 16mmol) and 4- dimethylamino pyrroles are added under ice-water bath Pyridine (145mg, 1.16mmol).It is stirred at room temperature 12 hours, dichloromethane (80mL × 3) extraction, saturated common salt washing (80mL), nothing Aqueous sodium persulfate is dried, and is removed solvent under reduced pressure, silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=20/1), is obtained White solid 1.88g, yield：79.4%.
LC-MS(pos.ion)m/z:204.06[M+1]+.
Step 3：Compound 3- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) hexamethylene The synthesis of formonitrile HCN
3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -4- amine (300mg, 0.98mmol) is dissolved in DMF In (25mL), continuously add 3- cyanocyclohexanoic base methanesulfonates (600mg, 2.96mmol), DMAP (120mg, 0.98mmol) and Cesium carbonate (1g, 2.96mmol).Under nitrogen protection, 90 DEG C are heated to, reaction 20h stops.Concentrated solvent, add saturated aqueous common salt (100mL), dichloromethane (50mL × 3) extraction.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=60/1), obtains Huang Color solid 250mg, yield：62.5%.
LC-MS:(pos.ion)m/z:411.19[M+1]+.
Embodiment 114
1- ((3R) -3- (4- amino -3- (11- hydroxyl -10,11- dihydro-dibenzos [b, f] oxa- Zhuo -2- bases) -1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (220mg, 0.55mmol) and the diphenyl hydrogens of 8- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -10,11- two And [b, f] oxa- Zhuo -10- alcohol (280mg, 0.83mmol), Pd (dppf) Cl2(40mg, 0.055mmol) and K2CO3(115mg, Isosorbide-5-Nitrae-dioxane (25mL) and water (5mL) are added after 0.83mmol) mixing, nitrogen is then replaced, is heated to react at 105 DEG C Overnight.Water (30mL) is added after reaction solution cooling, dichloromethane (30mL × 3) extracts, and organic phase anhydrous sodium sulfate drying is dense Crude on silica gel column chromatographic isolation and purification (DCM/MeOH (v/v)=15/1) after contracting, obtains gray solid 124mg, yield： 46.5%.
LC-MS:(pos.ion)m/z:483.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.26 (s, 1H), 7.81 (s, 1H), 7.55 (d, J=7.6Hz, 1H), 7.34 (d, J=8.3Hz, 1H), 7.30 (d, J=7.3Hz, 1H), 7.26-7.19 (m, 2H), 7.16-7.10 (m, 1H), 6.89-6.70 (m, 1H), 6.18-6.04 (m, 1H), 5.81 (d, J=5.7Hz, 1H), 5.73-5.59 (m, 1H), 5.10-5.04 (m,1H),4.80–4.63(m,1H),4.60–4.50(m,0.5H),4.33–4.16(m,1H),4.13–4.04(m,0.5H), 3.75–3.65(m,0.5H),3.33–3.27(m,2H),3.21–3.17(m,1H),3.03–2.94(m,0.5H),2.33–2.22 (m,1H),2.18–2.07(m,1H),1.96–1.89(m,1H),1.65–1.52(m,1H).
Embodiment 115
(R) -1- (3- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidines -1- carbonyls Base) cyclopropanecarbonitrile
Step 1：The synthesis of compounds methyl 2- cyan-acetic esters
Cyanoacetic acid (2.5g, 29mmol) is dissolved in methanol (50mL), the concentrated sulfuric acid is then slowly added into reaction solution (1.9mL,35mmol,Aldrich).70 DEG C are heated to, is reacted 12 hours.Stop heating, be cooled to room temperature, concentrated solvent.To Water (60mL) is added in reaction solution, adds sodium hydroxide solution (2M), adjusts pH to 7.Ethyl acetate extracts (60mL × 3), receives Collect organic phase, anhydrous sodium sulfate drying, filtering and concentrating.Obtain yellow liquid 2.0g, yield：69%.
LC-MS:(pos.ion)m/z:100.0[M+1]+.
Step 2：The synthesis of compounds methyl 1- anocy clopropyl formic acid esters
Caustic alcohol (824mg, 12.11mmol) is dissolved in ethanol (25mL), cyanoacetic acid is then added into reaction solution Methyl esters (800mg, 807mmol) and glycol dibromide (0.7mL, 8.07mmol).Nitrogen is protected, and is heated to 85 DEG C, reaction 4 is small When.Stop heating, be cooled to room temperature, water (60mL) is added into reaction solution, ethyl acetate extraction (60mL × 3), is collected organic Phase, anhydrous sodium sulfate drying, filtering and concentrating, obtain weak yellow liquid 582mg, yield：69%.
LC-MS:(pos.ion)m/z:126.1[M+1]+.
Step 3：The synthesis of compound 1- cyano group cyclopropane-carboxylic acids
Methyl 1- anocy clopropyls formic acid esters (500mg, 3.99mmol) is dissolved in ethanol (12mL), then to reaction Potassium hydroxide (290mg, 4.39mmol) is added in liquid.Reaction 3 hours is stirred at room temperature, after reaction completely, concentrated solvent, adds water (80mL) dilutes, and adds dilute hydrochloric acid solution (2M), regulation pH value of solution to 1, adds sodium chloride (10g).Dichloromethane extracts (50mL × 3) organic phase, is collected, anhydrous sodium sulfate drying, concentrated solvent, obtains weak yellow liquid 90mg, yield：20.2%.
LC-MS:(pos.ion)m/z:112.0[M+1]+.
Step 4：Compound (R) -1- (3- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- Base) piperidines -1- carbonyls) cyclopropanecarbonitrile synthesis
By (R) -3- (4- Phenoxyphenyls) -1- (piperidines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -4- amine (228mg, 0.58mmol) it is dissolved in dichloromethane (15mL), HATU (245mg, 0.64mmol), DIPEA is then added into reaction solution (0.11mL, 0.64mmol) and 1- cyano group cyclopropane-carboxylic acid (65mg, 0.59mmol).16 hours, after having reacted are stirred at room temperature, silicon Diatomaceous earth filters, and adds water (60mL) to dilute, and dichloromethane extraction (50mL × 3), collects organic phase, anhydrous sodium sulfate drying.Filtering, Concentrated solvent, silica gel column chromatography separating purification (DCM/MeOH (v/v)=35/1), obtains white solid product 41mg, yield： 14.6%.
LC-MS:(pos.ion)m/z:480.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.27 (s, 1H), 7.67 (d, J=8.5Hz, 2H), 7.44 (t, J= 7.9Hz, 2H), 7.19 (t, J=7.4Hz, 1H), 7.16 (d, J=8.5Hz, 2H), 7.13 (d, J=7.9Hz, 2H), 4.91- 4.73(m,1H),4.37–4.19(m,1H),3.66–3.58(m,1H),3.18–3.10(m,1H),2.31–2.22(m,1H), 2.19–2.11(m,1H),2.07–1.95(m,1H),1.84–1.67(m,1H),1.65–1.57(m,2H),1.57–1.45(m, 2H).
Embodiment 116
(R) -1- (3- (4- amino -3- (4- ((2- methyl butyl- 3- alkynes -2- bases) epoxide) phenyl) -1H- pyrazolos [3,4- D] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：Compound (R) -1- (3- (4- amino -3- (4- hydroxy phenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- Base) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (400mg, 1.0mmol) is dissolved in the in the mixed solvent of Isosorbide-5-Nitrae-dioxane (30mL) and water (7mL), then sequentially adds 4- hydroxy benzenes pinacol borate (331mg, 1.50mmol), potassium carbonate (210mg, 1.5mmol) and [double (diphenyl of 1,1'- Phosphorus) ferrocene] palladium chloride (73mg, 0.10mmol).Nitrogen is protected, and is heated to 105 DEG C, is reacted 12 hours.Stop heating, it is cold But to room temperature.Diatomite filters, concentrated solvent.Add water (50mL), dichloromethane extraction (50mL × 3).Collect organic phase, nothing Aqueous sodium persulfate is dried, and is filtered, concentration.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=12/1), obtains weak yellow liquid 247mg, yield：67.4%.
LC-MS:(pos.ion)m/z:365.2[M+1]+.
Step 2：Compound (R) -1- (3- (4- amino -3- (4- ((2- methyl butyl- 3- alkynes -2- bases) epoxide) phenyl) -1H- Pyrazolo [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (4- amino -3- (4- hydroxy phenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidines -1- Base) propyl- 2- alkene -1- ketone (90mg, 0.25mmol) is dissolved in DMF (15mL), continuously add the chloro- 3- methyl isophthalic acids-butine of 3- (50mg, 0.50mmol) and potassium carbonate (105mg, 0.74mmol).Under nitrogen protection, 70 DEG C are heated to, reacts 12h.Stop heating, cooling To room temperature, diatomite filtering, concentrated solvent.Silica gel column chromatography separating purification (DCM/MeOH (v/v)=45/1), obtains brown and consolidates Body 5mg, yield：4.7%.
LC-MS:(pos.ion)m/z:431.2[M+1]+.
Embodiment 117
(R) ((4- amino -3- (4- (3- phenoxy group propyl- 1- alkynes -1- bases) phenyl) -1H- pyrazolos [3,4-d] are phonetic by 3- by -1- Pyridine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：Compound (R)-tert-butyl group 3- (4- amino -3- (4- bromophenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- Base) piperidines -1- carboxylates synthesis
By (R)-tert-butyl group 3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidines -1- carboxylates (1.7g, 3.8mmol) is dissolved in the in the mixed solvent of glycol dimethyl ether (50mL) and water (12mL), then sequentially adds 4- bromines Phenyl boric acid (1g, 4.98mmol), potassium carbonate (1.1g, 7.7mmol) and four triphenyl phosphorus palladium chlorides (45mg, 0.038mmol). Nitrogen is protected, and is heated to stirring reaction 12 hours at 95 DEG C.Stop heating, be cooled to room temperature, filter, concentration.Silica gel column chromatography (DCM/MeOH (v/v)=40/1) is isolated and purified, obtains yellow solid 1.47g, yield：81%.
LC-MS:(pos.ion)m/z:474.1[M+1]+.
Step 2：Compound (R) -3- (4- bromophenyls) -1- (piperidines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -4- amine Synthesis
By (R)-tert-butyl group 3- (4- amino -3- (4- bromophenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidines -1- Carboxylate (1.47g, 3.11mmol) is dissolved in dioxane (30mL), and hydrochloric acid (4M, 30mL) is then added into reaction solution. It is stirred at room temperature 16 hours, after having reacted, adds dilute sodium hydrate aqueous solution, is adjusted to pH=9, dichloromethane extraction (60mL × 3), saturated common salt washing (60mL × 3), anhydrous sodium sulfate drying, removes solvent, silica gel column chromatography separating purification (DCM/ under reduced pressure MeOH (v/v)=8/1), obtain white solid product 1.01g, yield：87.2%.
LC-MS(pos.ion)m/z:374.1[M+1]+.
Step 3：Compound (R) -1- (3- (4- amino -3- (4- bromophenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -3- (4- bromophenyls) -1- (piperidines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -4- amine (1.05g, 2.81mmol) it is dissolved in dichloromethane (70mL), adds triethylamine (0.60mL, 4.30mmol, 0.728g/mL).At 0 DEG C slowly Acryloyl chloride (0.28mL, 3.38mmol, 1.11g/mL) is added, reaction 20min is stirred at room temperature.After reaction completely, saturation is added Saline solution (80mL), dichloromethane extraction (60mL × 3), organic phase anhydrous sodium sulfate drying, concentration, silica gel column chromatography separation are pure Change (DCM/MeOH (v/v)=40/1), obtain white product 810mg, yield：67.4%.
LC-MS:(pos.ion)m/z:428.1[M+1]+.
Step 4：Compound (R) -1- (3- (4- amino -3- (4- (3- phenoxy group propyl- 1- alkynes -1- bases) phenyl) -1H- pyrazoles And [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (4- amino -3- (4- bromophenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) Propyl- 2- alkene -1- ketone (110mg, 0.26mmol) is dissolved in DMF (15mL), continuously add (propyl- 2- alkynes -1- bases epoxide) benzene (51mg, 0.39mmol), cuprous iodide (10mg, 0.053mmol), triethylamine (53mg, 0.52mmol) and bis-triphenylphosphipalladium palladium dichloride (18mg,0.026mmol).Under nitrogen protection, 80 DEG C of reaction 15h being heated to, stop heating, are cooled to room temperature, diatomite filters, Concentrated solvent, saturated aqueous common salt (50mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration. Silica gel column chromatography separating purification (DCM/MeOH (v/v)=40/1), obtains brown solid 74mg, yield：60%.
LC-MS:(pos.ion)m/z:479.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ (ppm) 8.27 (s, 1H), 7.68 (d, J=7.8Hz, 2H), 7.60 (d, J= 8.2Hz, 2H), 7.35 (t, J=8.0Hz, 2H), 7.07 (d, J=8.0Hz, 2H), 7.00 (t, J=7.3Hz, 1H), 6.86- 6.70(m,1H),6.20–6.00(m,1H),5.74–5.55(m,1H),5.09(s,2H),4.80–4.65(m,0.5H),4.58– 4.49(m,1H),4.19–4.04(m,0.5H),3.76–3.66(m,0.5H),3.25–3.13(m,1H),3.08–2.98(m, 0.5H),2.30–2.22(m,1H),2.18–2.07(m,1H),1.97–1.87(m,1H),1.64–1.54(m,1H).
Embodiment 118
(R) -1- (3- (4- amino -3- (4- (3- morpholine propyl- 1- alkynes -1- bases) phenyl) -1H- pyrazolos [3,4-d] pyrimidine - 1- yls) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound 4- (propyl- 2- alkynes -1- bases) morpholine
3- propargyl bromides (1.0g, 0.725mmol) are dissolved in THF (40mL), then add morpholine (0.8mL, 9.0mmol) and Anhydrous potassium carbonate (2.4g, 17mmol).Nitrogen is protected, and is heated to 70 DEG C, is reacted 12 hours.Stop heating, it is cold But to room temperature.Add water (80mL), dichloromethane extraction (50mL × 3).Organic phase is collected, anhydrous sodium sulfate drying, is filtered, it is dense Contracting.Silica gel column chromatography separating purification (PE/EtOAc (v/v)=8/1), obtains oily yellow liquid 392mg, yield：37.2%.
LC-MS:(pos.ion)m/z:126.1[M+1]+.
Step 2：The synthesis of compound 4- (3- (4- bromophenyls) propyl- 2- alkynes -1- bases) morpholine
Bromo-iodobenzene (400mg, 1.41mmol) will be dissolved in dry THF (25mL), then be added into reaction solution Cuprous iodide (16mg, 0.084mmol) and tetra-triphenylphosphine palladium (50mg, 0.043mmol), nitrogen protection.Under the conditions of ice-water bath, DBU (0.32mL, 2.1mmol) and 4- (propyl- 2- alkynes -1- bases) morpholine (195mg, 1.56mmol) are slowly added into above-mentioned solution In.Continue stirring reaction 1 hour, be warmed to room temperature, be then heated to 50 DEG C, react 12 hours.Stop heating, be cooled to room temperature, Filtering and concentrating, silica gel column chromatography separating purification (PE/EtOAc (v/v)=8/1), obtains oily yellow liquid 338mg, yield： 85.3%.
LC-MS:(pos.ion)m/z:281.0[M+1]+.
Step 3：Compound 4- (3- (4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) phenyl) propyl- 2- Alkynes -1- bases) morpholine synthesis
By 4- (3- (4- bromophenyls) propyl- 2- alkynes -1- bases) morpholine (335mg, 1.2mmol), connection boric acid pinacol ester (445mg,1.79mmol)、Pd(dppf)Cl21 is added after (90mg, 0.12mmol) and KOAc (352mg, 3.59mmol) mixing, 4- dioxane (35mL), nitrogen is replaced, be heated to 80 DEG C of reaction 13h.Stop heating, be cooled to room temperature, diatomite filtering is dense Contracting filtrate.Add water (30mL), dichloromethane (30mL × 3) extraction, organic phase anhydrous sodium sulfate drying, the thick production after concentration Thing obtains brown oil 287mg, yield through silica gel column chromatography separating purification (DCM/MeOH (v/v)=30/1)：73.3%.
LC-MS:(pos.ion)m/z:328.2[M+1]+.
Step 4：Compound (R) -1- (3- (4- amino -3- (4- (3- morpholine propyl- 1- alkynes -1- bases) phenyl) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (140mg, 0.35mmol), 4- (3- (4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) phenyl) propyl- 2- Alkynes -1- bases) morpholine (150mg, 0.46mmol), Pd (dppf) Cl2(26mg, 0.036mmol) and K2CO3(75mg,0.54mmol) Isosorbide-5-Nitrae-dioxane (20mL) and water (5mL) are added after mixing, then replaces nitrogen, is heated to react overnight at 105 DEG C.Reaction Water (30mL) is added after liquid cooling, dichloromethane (30mL × 3) extracts, and organic phase anhydrous sodium sulfate drying is thick after concentration Product obtains oily yellow solid 25mg, yield through silica gel column chromatography separating purification (DCM/MeOH (v/v)=35/1)：15.1%.
LC-MS:(pos.ion)m/z:472.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ (ppm) 8.27 (s, 1H), 7.67 (d, J=7.6Hz, 2H), 7.60 (d, J= 8.1Hz,2H),6.87–6.69(m,1H),6.17–6.04(m,1H),5.74–5.57(m,1H),4.80–4.65(m,1H), 4.59–4.51(m,0.5H),4.46(s,2H),4.28–4.14(m,1H),4.11–4.02(m,0.5H),3.78–3.69(m, 0.5H),3.68–3.59(m,4H),3.26–3.17(m,1H),3.09–3.00(m,0.5H),2.77–2.52(m,4H),2.34– 2.20(m,1H),2.18–2.08(m,1H),1.98–1.89(m,1H),1.67–1.53(m,1H).
Embodiment 119
(R) -1- (3- (4- amino -3- (4- (3- hydroxyl propyl- 1- alkynes -1- bases) phenyl) -1H- pyrazolos [3,4-d] pyrimidine - 1- yls) piperidin-1-yl) propyl- 2- alkene -1- ketone
By (R) -1- (3- (4- amino -3- (4- bromophenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) Propyl- 2- alkene -1- ketone (120mg, 0.28mmol) is dissolved in DMF (15mL), continuously adds propargyl alcohol (24mg, 0.42mmol), iodate Cuprous (11mg, 0.058mmol), triethylamine (57mg, 0.56mmol) and bis-triphenylphosphipalladium palladium dichloride (19mg, 0.027mmol).Under nitrogen protection, 85 DEG C of reaction 15h are heated to, stop heating, are cooled to room temperature, diatomite filters, and concentration is molten Agent, saturated aqueous common salt (50mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration.Silicagel column Chromatography purifies (DCM/MeOH (v/v)=40/1), obtains brown solid 11mg, yield：9.7%.LC-MS:(pos.ion) m/z:403.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.28 (s, 1H), 7.72-7.65 (m, 2H), 7.58 (d, J= 8.1Hz, 2H), 6.87-6.72 (m, 1H), 6.15-6.05 (m, 1H), 5.72-5.58 (m, 1H), 5.38 (t, J=6.0Hz, 1H), 4.76-4.68 (m, 1H), 4.57-4.52 (m, 0.5H), 4.35 (d, J=5.9Hz, 2H), 4.23-4.16 (m, 1H), 4.10–4.05(m,0.5H),3.75–3.67(m,0.5H),3.25–3.19(m,1H),3.07–3.01(m,0.5H),2.31– 2.24(m,1H),2.17–2.11(m,1H),1.96–1.90(m,1H),1.64–1.56(m,1H).
Embodiment 120
(R) ((4- amino -3- (4- ((1- hydroxy-cyclohexyls) acetenyl) phenyl) -1H- pyrazolos [3,4-d] are phonetic by 3- by -1- Pyridine -1- bases) piperidin-1-yl) propyl- 2- alkene -1- ketone
By (R) -1- (3- (4- amino -3- (4- bromophenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) Propyl- 2- alkene -1- ketone (120mg, 0.28mmol) is dissolved in DMF (15mL), continuously adds acetylene cyclohexanol (53mg, 0.43mmol), Cuprous iodide (11mg, 0.058mmol), triethylamine (57mg, 0.56mmol) and bis-triphenylphosphipalladium palladium dichloride (19mg, 0.027mmol).Under nitrogen protection, 85 DEG C of reaction 15h are heated to, stop heating, are cooled to room temperature, diatomite filters, and concentration is molten Agent, saturated aqueous common salt (50mL) is added, dichloromethane extraction (50mL × 3), anhydrous sodium sulfate drying, is filtered, concentration.Silicagel column Chromatography purifies (DCM/MeOH (v/v)=40/1), obtains brown solid 33mg, yield：24.7%.
LC-MS:(pos.ion)m/z:471.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.27 (s, 1H), 7.71-7.62 (m, 2H), 7.56 (d, J= 8.2Hz,2H),6.87–6.72(m,1H),6.16–6.05(m,1H),5.73–5.58(m,1H),5.49(s,1H),4.76– 4.67(m,1H),4.58–4.52(m,0.5H),4.26–4.18(m,1H),4.11–4.05(m,0.5H),3.75–3.68(m, 0.5H),3.24–3.19(m,1H),3.05–2.99(m,0.5H),2.31–2.24(m,1H),2.16–2.09(m,1H),1.97– 1.91(m,1H),1.90–1.84(m,2H),1.70–1.63(m,2H),1.62–1.58(m,1H),1.59–1.42(m,6H).
Embodiment 121
(R) -1- (3- (4- amino -3- (4- ethynyl phenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidines -1- Base) propyl- 2- alkene -1- ketone
Step 1：The synthesis of compound ((4- bromophenyls) acetenyl) trimethyl silane
(50mL) will be dissolved in dry THF to bromo-iodobenzene (2g, 7.07mmol), then add cuprous iodide (20mg, 0.11mmol) and bi triphenyl phosphorus palladium chloride (75mg, 0.11mmol).Replace nitrogen three times, under nitrogen protection, be slowly added to Triethylamine (5mL, 35.35mmol, 0.728g/mL) and trimethylsilyl acetylene (1.2mL, 8.48mmol, 0.69g/mL).Nitrogen is protected Shield, react at room temperature 24 hours.After reaction completely, filtering, filtrate is concentrated, add saturated aqueous common salt (60mL), ethyl acetate extraction (60mL × 3), merge organic phase, anhydrous sodium sulfate drying, filter, concentration.Silica gel column chromatography separating purification (PE), obtains white Solid 1.63g, yield：91.1%.
LC-MS(pos.ion)m/z:254.0[M+1]+.
Step 2：Compound trimethyl ((4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) phenyl) acetylene Base) silane synthesis
By ((4- bromophenyls) acetenyl) trimethyl silane (800mg, 3.16mmol), connection boric acid pinacol ester (1.2g, 4.74mmol)、Pd(dppf)Cl21,4- dioxies are added after (230mg, 0.32mmol) and KOAc (930mg, 9.48mmol) mixing Six rings (50mL), nitrogen is replaced, be heated to 80 DEG C of reaction 13h.Stop heating, be cooled to room temperature, diatomite filtering, concentration filter Liquid.Add water (50mL), dichloromethane (50mL × 3) extraction, organic phase anhydrous sodium sulfate drying, the crude product warp after concentration Silica gel column chromatography separating purification (PE/EtOAc (v/v)=30/1), obtains faint yellow solid 569mg, yield：59.9%.
LC-MS(pos.ion)m/z:301.2[M+1]+.
Step 3：Compound (R) -1- (3- (4- amino -3- (4- ethynyl phenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- Base) piperidin-1-yl) propyl- 2- alkene -1- ketone synthesis
By (R) -1- (3- (iodo- 1H- pyrazolos [3,4-d] pyrimidine -1- bases of 4- amino -3-) piperidin-1-yl) propyl- 2- alkene - 1- ketone (300mg, 0.75mmol), trimethyl ((4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) phenyl) second Alkynyl) silane (340mg, 1.13mmol), Pd (dppf) Cl2(55mg, 0.075mmol) and K2CO3(160mg, 1.13mmol) is mixed Isosorbide-5-Nitrae-dioxane (50mL) and water (10mL) are added after conjunction, nitrogen is then replaced, is heated to react 12 hours at 105 DEG C.Instead Liquid is answered to add water (30mL), dichloromethane (30mL × 3) extraction, organic phase anhydrous sodium sulfate drying, after concentration after cooling down Crude on silica gel column chromatographic isolation and purification (DCM/MeOH (v/v)=35/1), obtains oily yellow solid 95mg, yield： 33.8%.
LC-MS:(pos.ion)m/z:373.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 8.27 (s, 1H), 7.72-7.66 (m, 2H), 7.64 (d, J= 8.1Hz,2H),6.87–6.70(m,1H),6.15–6.03(m,1H),5.73–5.58(m,1H),4.77–4.65(m,1H), 4.56–4.50(m,0.5H),4.30(s,1H),4.23–4.14(m,1H),4.10–4.03(m,0.5H),3.76–3.68(m, 0.5H),3.25–3.18(m,1H),3.09–3.01(m,0.5H),2.31–2.22(m,1H),2.15–2.09(m,1H),1.95– 1.87(m,1H),1.63–1.53(m,1H).
By the similar synthetic method of the embodiment of the present invention, and the synthetic method described in the present invention, suitably may be used Initiation material is selected, the compound shown in table 1 is prepared：
The compound of table 1 and its characterize data
Biological Examples 1BTK external activity test methods
Experimental method：
1.1 × kinase buffer liquid and termination test buffer are prepared
(1) 1 × kinase buffer liquid (50mM HEPES, pH 7.5,0.01%Brij-35,10mM MgCl2,2mM DTT)；
(2) test buffer (100mM HEPES, pH 7.5,0.015%Brij-35,0.2%Coating is terminated Reagent#3,50mM EDTA)。
2. the compound of test kinase prepares：Compound serial dilution
(1) using 100%DMSO by 50 times of diluted chemical compound to highest final concentration, by the compound of the 100 μ L concentration Solution is transferred to a hole of 96 orifice plates；If compound starts to test in 10000nM, prepare 500 μM of compounds in this step DMSO solution；
(2) by 4 times of compound serial dilution, totally 10 concentration gradients；
(3) 100 μ L 100%DMSO solution are added in two emptying apertures, compareed as without compound control and without enzyme, It is source plate to mark this plate；
(4) intermediate plate is prepared：Each concentration compounds of 10 μ L are transferred to intermediate plate from source plate respectively, and add 90 μ 1 × kinase buffer liquids of L, vibration mix 10min.
3. preparing experiment plate
Corresponding aperture transferase 45 μ L compound solutions are into corresponding 384 orifice plate from the intermediate plate of 96 orifice plates；For example, 96 holes A1 in plate is transferred to the A1 and A2 of 384 orifice plates, and the A2 in 96 orifice plates is transferred to the A3 and A4 of 384 orifice plates, by that analogy.
4. kinase reaction
(1) 2.5 × enzyme solutions are prepared：Enzyme is added in 1 × kinase buffer liquid；
(2) 2.5 × peptide solution is prepared：FAM-labeled peptide and ATP are added in 1 × kinase buffer liquid；
Containing the compound solution that 5 μ L DMSO contents are 10% in (3) 384 hole brassboards；
(4) 10 μ 2.5 × enzyme solutions of L are added to 384 holes containing the compound solution that 5 μ L DMSO contents are 10% In brassboard；
(5) it is incubated at room temperature 10min；
(6) 10 2.5 × peptide solutions of μ L are added in 384 hole brassboards；
(7) kinase reaction and termination：28 DEG C are incubated 1 hour, add 25 μ L stop buffer terminating reactions.
5. DATA REASONING
Read data and collect.
6. curve matching
(1) data of copy and converted measurement；
(2) inhibiting rate is converted to：
Inhibiting rate=(maximum-sample value)/(maximum-minimum value) * 100；
Wherein " maximum " is DMSO control values；" minimum value " is without kinase control hole count value.
(3) enter data into corresponding analysis software Xlfit and draw IC50Value, experimental result are shown in Table 2.
The enzyme (BTK) of the compound of table 2 suppresses data
Embodiment BTK IC50(nM) Embodiment BTK IC50(nM) Embodiment BTK IC50(nM)
Embodiment 1 8.79 Embodiment 2 3.00 Embodiment 3 7.06
Embodiment 6 5.33 Embodiment 7 10.04 Embodiment 15 6.97
Embodiment 16 3.16 Embodiment 19 13.00 Embodiment 20 11.00
Embodiment 23 9.09 Embodiment 29 13.58 Embodiment 34 7.03
Embodiment 38 7.52 Embodiment 39 6.17 Embodiment 45 12.47
Embodiment 46 5.01 Embodiment 47 2.13 Embodiment 51 11.44
Embodiment 52 9.24 Embodiment 53 10.76 Embodiment 57 10.47
Embodiment 62 9.39 Embodiment 64 6.04 Embodiment 65 3.68
Embodiment 66 9.53 Embodiment 74 11.27 Embodiment 105 13.26
Embodiment 121 12.12
Conclusion：The data of table 2 show that the embodiment of the present invention has stronger inhibitory action to BTK.Embodiment in table 2 is this The Typical Representative of invention compound, other compounds of the invention also have stronger inhibitory action to BTK.
PK is studied in the test compound rat body of biological Examples 2
Gavage gives 5mg/kg to male SD rat by oral administration or hind leg peduncular veins injects 1mg/kg test compound.Administration Temporally point (0.083,0.25,0.5,1,2,5,7 and 24h) tail vein blood, blood sampling volume were 200~400 μ L/ time points afterwards, It is collected in and adds K2In EDTA anticoagulant tube.Sample is in 60min, 12000rpm, 4 DEG C, centrifuges 2min, separated plasma, and store It is to be measured in -80 DEG C.Plasma sample is after liquid-liquid extraction, on triple quadrupole bar tandem mass spectrometer, with multiple reaction ion monitoring (MRM) mode carries out quantitative analysis.Using the softwares of WinNonlin 6.3, non-compartment model method calculates pharmacokinetic parameters.
Conclusion：Removing speed is slower in the compounds of this invention body, intravenous and oral long half time, and bioavilability is high.

Claims (14)

1. a kind of compound, its for compound shown in the compound or formula (II) as shown in formula (II) stereoisomer, geometry Isomers, dynamic isomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug：
Wherein：
X is C1-8Alkylidene or C1-8Sub- miscellaneous alkyl；X is optionally by 1,2,3,4,5,6,7,8,9,10,11,12,13 or 14 RXInstitute Substitution；
Each RXIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Alkoxy or C1-6Alkylamino；
Cy1 is C3-8Cycloalkyl, C3-8Cycloalkenyl group, C2-10Heterocyclic radical, C6-10Aryl or C1-9Heteroaryl；Cy1 is optionally by 1,2,3, 4th, 5,6,7,8,9 or 10 substituents are substituted, and the substituent is selected from RA1、RA2、RA3、RA4、RA5Or RA6；
Each RA1、RA2、RA3、RA4、RA5And RA6Independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, Aldehyde radical, oxo (=O) ,-C (=O)-NRcRd,-S (=O)2-NRcRd、C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Alkoxy, C1-6Alkylamino, halo C1-6Alkyl, halo C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, cyano group take The C in generation1-6Alkyl, the C of cyano group substitution1-6Alkoxy, the C of cyano group substitution1-6Alkylamino, the C of hydroxyl substitution1-6Alkyl, hydroxyl take The C in generation1-6Alkoxy, the C of hydroxyl substitution1-6Alkylamino, C3-6Cycloalkyl, C3-6Cycloalkenyl group, C2-8Heterocyclic radical, C6-10Aryl, C1-9 Heteroaryl, C3-6Cycloalkyl C1-6Alkyl, C3-6Cycloalkenyl group C1-6Alkyl, C2-8Heterocyclic radical C1-6Alkyl, C6-10Aryl C1-6Alkyl, C1-9 Heteroaryl C1-6Alkyl, C3-6Cycloalkyl amino, C3-6Cycloalkenyl group amino, C2-8Heterocyclylamino group, C6-10Fragrant amino, C1-9Heteroaryl Amino, C3-6Cycloalkyl oxy, C3-6Cycloalkenyl oxy, C2-8Heterocyclic radical epoxide, C6-10Aryloxy group, C1-9Heteroaryl epoxide, C3-6Ring Alkyl oxy C1-6Alkyl, C3-6Cycloalkenyl oxy C1-6Alkyl, C2-8Heterocyclic radical epoxide C1-6Alkyl, C6-10Aryloxy group C1-6Alkyl, C1-9Heteroaryl epoxide C1-6Alkyl, C3-6Cycloalkyl C1-6Alkoxy, C3-6Cycloalkenyl group C1-6Alkoxy, C2-8Heterocyclic radical C1-6Alcoxyl Base, C6-10Aryl C1-6Alkoxy or C1-9Heteroaryl C1-6Alkoxy；Each RA1、RA2、RA3、RA4、RA5And RA6Individually optionally by 1, 2nd, 3,4,5 or 6 R1Substituted；
Each R1It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Alkoxy, C1-6Alkylamino, C1-6Alkyl sulphonyl, halo C1-6Alkyl, halo C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, the C of cyano group substitution1-6Alkyl, the C of cyano group substitution1-6Alkoxy, cyano group Substituted C1-6Alkylamino, the C of hydroxyl substitution1-6Alkyl, the C of hydroxyl substitution1-6Alkoxy or the C of hydroxyl substitution1-6Alkylamino；
Each RcAnd RdIt independently is hydrogen, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkyl, C3-8Cycloalkenyl group, C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C3-8Cycloalkyl C1-6Alkyl, C3-8Cycloalkenyl group C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C6-10Virtue Base C1-6Alkyl or C1-9Heteroaryl C1-6Alkyl；Each RcAnd RdIndividually optionally by 1,2,3,4,5 or 6 R2Substituted；
Each R2It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), C1-6Alkyl, Halo C1-6Alkyl, the C of hydroxyl substitution1-6Alkyl, the C of cyano group substitution1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Alkoxy or C1-6Alkylamino；
S is 0,1,2,3,4,5 or 6；
Hy is C3-8Cycloalkylidene, C3-8Sub- cycloalkenyl group, C2-15Sub- heterocyclic radical, C6-10Arlydene or C1-9Inferior heteroaryl；
RBThe C substituted for cyano group or cyano group1-6Alkyl；Or RBFor following subformula：
Ry1、Ry4And Ry3It is each independently hydrogen, halogen, methyl or cyano group；
Cy3 is C3-6Cycloalkylidene, C3-6Sub- cycloalkenyl group, C2-6Sub- heterocyclic radical, C6-10Arlydene or C1-6Inferior heteroaryl；
Each R3、R3aAnd R12It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, carboxyl or C1-3Alkyl；
Each R4、R3b、R5、R13And R14It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, carboxyl ,-(CRiRk)n-NRvRw、C1-3Alkane Base, halo C1-3Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Alkoxy C1-4Alkyl, C1-3Alkylamino C1-3Alkyl, C3-6Cycloalkyl, C3-6Cycloalkyl C1-3Alkyl, C2-6Heterocyclic radical, C2-6Heterocyclic radical C1-3Alkyl, C6-10Aryl, C6-10Aryl C1-3Alkyl, C1-6Heteroaryl Or C1-6Heteroaryl C1-3Alkyl；
R18And R19It is each independently hydrogen, deuterium, C1-4Alkyl, halo C1-3Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-3Alkoxy C1-3 Alkyl, C1-3Alkylamino C1-3Alkyl, C3-6Cycloalkyl, C3-6Cycloalkyl C1-3Alkyl, C2-6Heterocyclic radical C1-3Alkyl, C6-10Aryl C1-3 Alkyl or C1-6Heteroaryl C1-3Alkyl；
Each R27、R28And R30It independently is hydrogen, C1-4Alkyl, halo C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-3Alkoxy C1-3Alkane Base, C1-3Alkylamino C1-3Alkyl, C3-6Cycloalkyl, C3-6Cycloalkyl C1-3Alkyl, C2-6Heterocyclic radical C1-3Alkyl, C6-10Aryl C1-3Alkane Base or C1-6Heteroaryl C1-3Alkyl；
Each RiAnd RkIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), C1-3Alkane Base, C2-4Alkenyl or C2-4Alkynyl；
N is 1,2,3,4,5 or 6；
Each R3c、R3d、RvAnd RwIt independently is hydrogen, deuterium, C1-4Alkyl, the C of cyano group substitution1-3Alkyl, halo C1-3Alkyl, C1-3Alcoxyl Base C1-3Alkyl, C3-6Cycloalkyl, C6-10Aryl, C1-6Heteroaryl, C2-6Heterocyclic radical or C2-6Heterocyclic radical C1-3Alkyl；Or Rv、RwWith with Connected N atoms formed together by the 3-8 molecular heterocycle of original；With
Each X, RX、Cy1、Cy3、RA1、RA2、RA3、RA4、RA5、RA6、Rc、Rd、R1、R2、Hy、RB、R3、R3a、R3b、R3c、R3d、R4、R5、 R12、R13、R14、R18、R19、R27、R28、R30、Ri、Rk、RvAnd RwIndividually optionally by 1,2,3,4,5,6,7,8,9 or 10 substitution Base is substituted, the substituent be selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), C1-6Alkyl, C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Alkyl-C (=O)-, cyano group substitution C1-6Alkyl-C (=O)-, C1-6Alkylamino, NH2- S (=O)2-、C1-6Alkyl-NH-S (=O)2-、NH2- S (=O)2-C1-6Alkyl, halo C1-6Alkyl, hydroxyl Substituted C1-6Alkyl, the C of cyano group substitution1-6Alkyl, C3-6Cycloalkyl, C2-8Heterocyclic radical, C6-10Aryl, C6-10Aryloxy group or C6-10 Aryl C1-6Alkoxy.
2. compound according to claim 1, wherein Hy are C3-6Cycloalkylidene, C3-6Sub- cycloalkenyl group, C6-10Arlydene, C1-6 Inferior heteroaryl or Hy are following subformula：
Wherein：
p1And p2It is each independently 0,1 or 2；Or wherein Hy is following subformula：
3. compound according to claim 1, wherein RBThe C substituted for cyano group or cyano group1-4Alkyl；Or RBFor following sub- knot Structure formula：
4. compound according to claim 1, it is compound shown in the compound or formula (IIa) as shown in formula (IIa) Stereoisomer, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvate, metabolite with And pharmaceutically acceptable salt or prodrug：
5. compound according to claim 1, wherein Cy1 are C3-6Cycloalkyl, C3-6Cycloalkenyl group, C2-8Heterocyclic radical, C6-10Virtue Base or C1-9Heteroaryl；Cy1 is optionally substituted by 1,2,3,4,5,6,7,8,9 or 10 substituent, and the substituent is selected from RA1、RA2、RA3、RA4、RA5Or RA6。
6. compound according to claim 1, wherein Cy1 are cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclobutane Base, cyclopentenyl, cyclopentadienyl group, cyclohexenyl group, cyclohexadienyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, 1- Oxo thio-morpholinyl, 1,1- dioxothiomorpholinyls or iso-indoles -1,3- diketone -4- bases；Or Cy1 is following minor structure Formula：
Cy1 is optionally substituted by 1,2,3,4,5,6,7,8,9 or 10 substituent, and the substituent is selected from RA1、RA2、RA3、RA4、RA5Or RA6。
7. compound according to claim 1, it is compound shown in the compound or formula (IV) as shown in formula (IV) Stereoisomer, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and Pharmaceutically acceptable salt or prodrug：
Wherein：
Y1For N or CRA1；
Y2For N or CRA2；With
Y3For N or CRA3。
8. according to the compound described in claim 1,4 or 7, wherein X is-(CR31R32)r-、-(CR31R32)r-O- (CR33R34)t-、-(CR31R32)r- C (=O)-(CR33R34)t-、-(CR31R32)r- S (=O)2-(CR33R34)t-、-(CR31R32)r- N(R35)-(CR33R34)t- ,-C (=O)-N (R35)-(CR33R34)t-、-(CR31R32)r-N(R35)-C (=O)-or-(CR31R32)r- N(R35)-S (=O)2-；
Each r independently is 1,2,3 or 4；
Each t independently is 0,1,2 or 3；
Each R31、R32、R33And R34Independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (= O)、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-3Alkoxy or C1-3Alkylamino；With
Each R35It independently is hydrogen, deuterium, C1-4Alkyl, C2-4Alkenyl or C2-4Alkynyl；Or wherein X is-CH2-、-(CH2)2-、- (CH2)3-、-C(CH3)2-、-CH2-C(CH3)2-、-C(CH3)(OH)-、-CH2-O-、-CH2-O-CH2-、-C(CH3)2-O-、-C (CH3)(OH)-O-、-CH(CH3)-O-CH2-、-C(CH3)2-O-CH2-、-CH2-NH-、-CH2-NH-CH2-、-C(CH3)2-NH-、- CH(CH3)-NH-CH2-、-C(CH3)2-NH-CH2-、-C(CH3) (OH)-NH- ,-C (=O)-NH- ,-C (=O)-NH-CH2-、- CH2- NH-C (=O)-,-CH2- NH-S (=O)2-、-(CH2)2- NH-S (=O)2-、-CH(CH3)-NH-S (=O)2- or-C (CH3)2- NH-S (=O)2-。
9. according to the compound described in claim 1,4 or 7, wherein each RA1、RA2、RA3、RA4、RA5And RA6Independently be hydrogen, deuterium, Fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, aldehyde radical, oxo (=O) ,-C (=O)-NRcRd,-S (=O)2- NRcRd、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Alkoxy, C1-4Alkylamino, halo C1-4Alkyl, halo C1-4Alkoxy, C1-4Alkoxy C1-4Alkyl, C1-4Alkylamino C1-4Alkyl, the C of cyano group substitution1-4Alkyl, the C of cyano group substitution1-4Alkoxy, cyano group Substituted C1-4Alkylamino, the C of hydroxyl substitution1-4Alkyl, the C of hydroxyl substitution1-4Alkoxy, the C of hydroxyl substitution1-4Alkylamino, C3-6 Cycloalkyl, C3-6Cycloalkenyl group, C2-6Heterocyclic radical, C6-10Aryl, C1-6Heteroaryl, C3-6Cycloalkyl C1-3Alkyl, C3-6Cycloalkenyl group C1-3Alkane Base, C2-6Heterocyclic radical C1-3Alkyl, C6-10Aryl C1-3Alkyl, C1-6Heteroaryl C1-3Alkyl, C3-6Cycloalkyl amino, C3-6Cycloalkenyl group Amino, C2-6Heterocyclylamino group, C6-10Fragrant amino, C1-6Heteroaryl amino, C3-6Cycloalkyl oxy, C3-6Cycloalkenyl oxy, C2-6It is miscellaneous Ring group epoxide, C6-10Aryloxy group, C1-6Heteroaryl epoxide, C3-6Cycloalkyl oxy C1-3Alkyl, C3-6Cycloalkenyl oxy C1-3Alkyl, C2-6Heterocyclic radical epoxide C1-3Alkyl, C6-10Aryloxy group C1-4Alkyl, C1-6Heteroaryl epoxide C1-3Alkyl, C3-6Cycloalkyl C1-3Alcoxyl Base, C3-6Cycloalkenyl group C1-3Alkoxy, C2-6Heterocyclic radical C1-3Alkoxy, C6-10Aryl C1-4Alkoxy or C1-6Heteroaryl C1-4Alcoxyl Base；Each RA1、RA2、RA3、RA4、RA5And RA6Individually optionally by 1,2,3,4,5 or 6 R1Substituted；
Each R1It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Alkoxy, C1-4Alkylamino, C1-4Alkyl sulphonyl, halo C1-4Alkyl, halo C1-4Alkoxy, C1-4Alkoxy C1-4Alkyl, C1-4Alkylamino C1-4Alkyl, the C of cyano group substitution1-4Alkyl, the C of cyano group substitution1-4Alkoxy, cyano group Substituted C1-4Alkylamino, the C of hydroxyl substitution1-4Alkyl, the C of hydroxyl substitution1-4Alkoxy or the C of hydroxyl substitution1-4Alkylamino；
Each RcAnd RdIt independently is hydrogen, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-6Cycloalkyl, C3-6Cycloalkenyl group, C2-6Heterocyclic radical, C6-10Aryl, C1-5Heteroaryl, C3-6Cycloalkyl C1-3Alkyl, C3-6Cycloalkenyl group C1-3Alkyl, C2-6Heterocyclic radical C1-3Alkyl, C6-10Aryl C1-3Alkyl or C1-5Heteroaryl C1-3Alkyl；Each RcAnd RdIndividually optionally by 1,2,3,4,5 or 6 R2Substituted；With
Each R2It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), C1-3Alkyl, C2-3Alkenyl, C2-3Alkynyl, C1-3Alkoxy or C1-3Alkylamino；Or wherein each RA1、RA2、RA3、RA4、RA5And RA6Independently be hydrogen, Deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, aldehyde radical, oxo (=O), Ph-NH-C (=O)-, halogen substitution Ph-NH-C (=O)-, Ph-NH-S (=O)2-, it is methyl, ethyl, propyl group, isopropyl, methoxyl group, ethyoxyl, propoxyl group, different Propoxyl group, methylamino, dimethylamino, ethylamino, halo C1-3Alkyl, halo C1-3Alkoxy, cyclopropyl, cyclobutyl, cyclopenta, Cyclohexyl, oxetanylmethoxy, azelidinyl, tetrahydrofuran base, pyrrolidinyl, THP trtrahydropyranyl, piperidyl, piperazinyl, Quinoline base, thio-morpholinyl, phenyl, indenyl, phenoxy group, thiazol-2-yl epoxide, thiazole-4-yl epoxide, thiazole -5- bases epoxide, pyrrole Piperidinyl epoxide, pyrimidine radicals epoxide, pyrazinyl epoxide, pyridazinyl epoxide, benzyloxy, fluorinated benzyloxy, chloro benzyloxy, cyano group take Benzyloxy, benzyloxy, phenyl ethoxy, phenoxymethyl, fluorinated phenoxy methyl, the chlorobenzene oxygen of mesyl substitution in generation Ylmethyl, pyridine -2- ylmethoxies, pyridin-3-yl methoxyl group, pyridin-4-yl methoxyl group, pyrimidinylmethoxy, pyrazinyl first Epoxide, pyridazinylmethoxy, thiazol-2-yl methoxyl group, thiazole-4-yl methoxyl group, thiazole -5- ylmethoxies, 2- methylthiazols - 5- ylmethoxies or 5- methylthiazol -2- ylmethoxies.
10. compound according to claim 1, it is for the compound with one of following structure or with one of following knot The stereoisomer of structure compound, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, Pharmaceutically acceptable salt or prodrug：
11. a kind of pharmaceutical composition, comprising the compound described in claim 1-10 any one, it is further comprising pharmaceutically Acceptable carrier, excipient, diluent, at least one of assistant agent or medium；Or/and
It further includes additional therapeutic agent, and it is selected from chemotherapeutic agent, cytotoxic drug, antibody drug, signal and turned Lead inhibitor, chemotherapeutics, antiproliferative, anti-inflammatory agent, immunomodulator or immunodepressant, neurotrophic factor, for treating The activating agent of angiocardiopathy, the activating agent for treating diabetes and the activating agent for treating autoimmune disease.
12. pharmaceutical composition according to claim 11, replace Buddhist nun wherein the additional therapeutic agent is selected from according to Shandong, take fluorine rice Spy, Carfilzomib, Rituximab, difficult to understand, Cetuximab, Victibix, matuzumab, Buddhist nun's trastuzumab, Herceptin, Nivolumab, bendamustine, fludarabine, Imatinib, Dasatinib, Gefitinib, nilotinib, Erlotinib, Lapatinib, Sorafenib, Sutent, Conmana, hydrochloric acid Conmana, HKI-272, canertinib, ZD6474, Axitinib, Xi Li for Buddhist nun, according to pyrrole for Buddhist nun, west for Buddhist nun, tropsch imatinib, Luso for Buddhist nun, Baricitinib, Pacritinib、Momelotinib、Peficitinib、Obinutuzumab、Acalabrutinib、Spebrutinib、 inotuzumab ozogamicin、Obinutuzumab、Duvelisib、Idelalisib、PRN-1008、HM-71224、 ONO-4059、BGB-3111、ML-319、TAS-5315、AT-9283、X-022、AC-0025、NS-018、INCB-39110、 JTE-052, R-348 or combinations thereof.
13. the drug regimen described in compound or claim 11-12 any one described in claim 1-10 any one Purposes of the thing in medicine is prepared, wherein the medicine is used to preventing, handle, treat or mitigating autologous patient immunological diseases, inflammation Property disease, cancer or other diseases；Wherein autoimmune disease is lupus, multiple sclerosis, muscle contracting lateral sclerosis, class wind Wet arthritis, psoriasis, type i diabetes, the complication caused by organ transplant, foreign matter transplanting, diabetes, cancer, asthma, Atopic dermatitis, AITD, ulcerative colitis, Crohn disease, Alzheimer disease, leukaemia or lymph Knurl；Wherein inflammatory disease is keratitis, rhinitis, stomatitis, parotitis, pharyngitis, tonsillitis, tracheitis, bronchitis, lung Inflammation, myocarditis, gastritis, enterogastritis, cholecystitis or appendicitis；Wherein cancer or other diseases are small lymphocyte lymthomas, anxious Property lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, acute morning Myelocyte leukaemia, chronic myelocytic leukemia, diffusivity large B cell lymphoid tumor, intravascular large B cell lymphoma are primary Property effusion lymphoma, Waldenstrom's macroglobulinemia, follicular lymphoma, Huppert's disease and lymphoma mantle cell and its His protein kinase mediated disease.
14. a kind of usage right is required described in compound or claim 11-12 any one described in 1-10 any one Pharmaceutical composition come prepare for suppress or regulatory protein kinase activity medicine purposes；Wherein described protein kinase is BTK.
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CN111454268A (en) * 2019-01-18 2020-07-28 明慧医药（上海）有限公司 Cyclic molecules as inhibitors of bruton's tyrosine kinase
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WO2022033532A1 (en) * 2020-08-13 2022-02-17 上海和誉生物医药科技有限公司 Fgfr and mutation inhibitor thereof, and preparation method therefor and use thereof
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RU2811207C1 (en) * 2020-08-13 2024-01-11 Аббиско Терапеутикс Ко., Лтд. Fgfr and its mutation inhibitor, method of its preparation and use
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